Certain substituted polyketides, pharmac eutical compositions containing them and their use in treating tumors

ABSTRACT

The present invention relates to certain substituted polyketides of formula I,  
                 
 
     wherein A, B and C are as defined herein, pharmaceutical compositions containing said compounds, and the use of said compounds in treating tumors.

[0001] This application claims the benefit of Provisional ApplicationNo. 60/343,394, filed Dec. 21, 2001, and Provisional Application No.60/332,399, filed Nov. 16, 2001, both of the contents of which areincorporated herein by reference.

FIELD OF THE INVENTION

[0002] The present invention relates to the area of chemotherapeuticagents and, more particularly, relates to certain substitutedpolyketides, and the use of said polyketides in treating tumors.

BACKGROUND OF THE INVENTION

[0003] Cancer is a serious health problem throughout the world. Forexample, cancer incidence in the U.S. has increased 30% during the past30 years, and is expected to continue to increase into the next century.This is attributable to the increased prevalence of cigarette smoking inwomen compared to men, general aging of the population, and enhanceddiagnostic capabilities, as well as potential decreases in mortalityfrom other causes. As a result, an extensive number of researchendeavors has been undertaken in an effort to develop therapiesappropriate to the treatment and alleviation of cancer in humans.

[0004] In the chemotherapeutic area, research has been conducted todevelop anti-tumor agents effective against various types of cancer.Oftentimes, anti-tumor agents which have been developed and foundeffective against cancer cells are, unfortunately, also toxic to normalcells. This toxicity manifests itself in weight loss, nausea, vomiting,hair loss, fatigue, itching, hallucinations, loss of appetite, etc.,upon administration of the anti-tumor agent to a patient in need ofcancer chemotherapy.

[0005] Furthermore, conventionally used chemotherapeutic agents do nothave the effectiveness desired or are not as broadly effective againstdifferent types of cancers as desired. As a result, a great need existsfor chemotherapeutic agents which are not only more effective againstall types of cancer, but which have a higher degree of selectivity forkilling cancer cells with no or minimal effect on normal healthy cells.In addition, highly effective and selective anti-tumor agents, inparticular, against cancers of the colon, bladder, prostate, stomach,pancreas, breast, lung, liver, brain, testis, ovary, cervix, skin, vulvaand small intestine are desired. Moreover, anti-tumor activity againstcolon, breast, lung and prostate cancers as well as melanomas areparticularly desired because of the lack of any particular effectivetherapy at the present time.

[0006] (+)-Discodermolide is a novel polyketide natural product that wasisolated from extracts of the marine sponge Discodermia dissoluta byresearchers at the Harbor Branch Oceanographic Institution (HBOI)(Gunasekera S P, Gunasekera M, Longley R E, Schulte G K. Discodermolide:a new bioactive polyhydroxylated lactone from the marine spongeDiscodermia dissoluta. [published erratum appears in J. Org. Chem.1991;56:1346]. J. Org. Chem. 1990;55:4912-15.). Discodermolide lacksobvious structural resemblance to paclitaxel, yet it shares withpaclitaxel (the active substance in the drug Taxol) the ability tostabilize microtubules. In mechanism-based assays, discodermolide ismore effective than paclitaxel. In fact, of the handful of compoundsknown to induce polymerization of purified tubulin, discodermolide isthe most potent. However, microtubules, the major structural componentin cells, are not simple equilibrium polymers of tubulin. They exist asregulated GTP-driven dynamic assemblies of heterodimers of α and βtubulin. Although the dynamics are relatively slow in interphase cells,upon entering mitosis, the rate of growing and shortening increases 20-to 100-fold—the average microtubule turns over half the tubulin subunitsevery ten seconds. This change in rate allows the cytoskeletalmicrotubule network to dismantle and a bipolar spindle-shaped array ofmicrotubules to assemble. The spindle attaches to chromosomes and movesthem apart. The response to complete suppression of microtubule dynamicsin cells is death. However, mitotic cells are more sensitive and thetolerance threshold appears to be cell-type specific. Molecules likepaclitaxel that bind with high affinity to microtubules disrupt thedynamics process in tumor cells with lethal results even when the ratioof bound drug to tubulin is very low. Discodermolide binds to tubulincompetitively with paclitaxel. Since paclitaxel has proven to be usefulin treating some cancers, other compounds of the same mechanistic classmay have utility against hyperproliferative disorders.

[0007] Development of discodermolide or structurally related analoguesis hindered by the lack of a reliable natural source of the compound ora feasible synthetic route. Naturally occurring discodermolide is scarceand harvesting the producing organism presents logistical problems.There is an ever-growing need for improved syntheses that enableproduction of multi-gram amounts of discodermolide and structurallyrelated analogues.

DESCRIPTION OF THE PRIOR ART

[0008] Martello L A, LaMarche M J, He L, Beauchamp T J, Smith A B,Horwitz S B. The relationship between Taxol and (+)-discodermolide:synthetic analogs and modeling studies. Chem. Biol. 2001;8(9):843-855.

[0009] Nerenberg J B, Hung D T, Somers P K, Schreiber S L. Totalsynthesis of the immunosuppressive agent (−)-discodermolide. J. Am.Chem. Soc. 1993;115:12621-622.

[0010] Hung D T, Nerenberg J B, Schreiber S L. Syntheses ofdiscodermolides useful for investigating microtubule binding andstabilization. J. Am. Chem. Soc. 1996;118:11054-11080.

[0011] Smith A B, Qiu Y, Jones D R, Kobayashi K. Total synthesis of(−)-discodermolide. J. Am. Chem. Soc. 1995; 117:12011-12012.

[0012] Harried S S, Yang G, Strawn M A, Myles D C. Total synthesis of(−)-discodermolide: an application of a chelation-controlled alkylationreaction., J. Org. Chem. 1997;62:6098-6099.

[0013] Marshall J A, Johns B A. Total synthesis of (+)-discodermolide.J. Org. Chem. 1998;63:7885-7892.

[0014] Halstead D P. I. Total synthesis of (+)-miyakolide II. Totalsynthesis of (−)-discodermolide III. Total synthesis of(+)-discodermolide (dissertation). Cambridge (Mass): Harvard University,1998.

[0015] Smith A B III, Kaufman M D, Beauchamp T J, LaMarche M J, ArimotoH. Gram-Scale Synthesis of (+)-Discodermolide. Org. Lett.1999;1:1823-1826.

[0016] Paterson I, Florence G J, Gerlach K, Scott J. Total synthesis ofthe antimicrotubule agent (+)-discodermolide using boron-mediated aldolreactions of chiral ketones. Angew. Chem., Int. Ed. 2000;39:377-380.

[0017] Smith A B III, Qiu Y, Kaufman M, Arimoto H, Jones D R, KobayashiK, Beauchamp T J. Preparation of intermediates for the synthesis ofdiscodermolides and their polyhydroxy dienyl lactone derivatives forpharmaceutical use. U.S. (2000), 83 pp., Cont.-in-part of U.S. Pat. No.5,789,605. CODEN: USXXAM U.S. Pat. No. 6,096,904 A 20000801 CAN133:135166 AN 2000:531688.

[0018] Smith A B III, Qiu Y, Kaufman M, Arimoto H, Jones D R, KobayashiK, Beauchamp, T J. Preparation of intermediates for the synthesis ofdiscodermolides and their polyhydroxy dienyl lactone derivatives forpharmaceutical use. PCT Int. Appl. (2000), 201 pp. CODEN: PIXXD2 WO0004865 A220000203 CAN 132:137207 AN 2000:84572.

[0019] Smith A B III Qiu Y, Kaufman M, Arimoto H, Jones D R, KobayashiK. Synthetic techniques and intermediates for polyhydroxydienyllactonesand mimics thereof. PCT Int. Appl. (1998), 194 pp. CODEN: PIXXD2 WO9824429 Al 19980611 CAN 129:67649 AN 1998:394202.

[0020] Gunasekera S P, Longley R E. Synthesis, antitumor activity andformulations of discodermolide acetates. U.S. (2000), 9 pp. CODEN:USXXAM U.S. Pat. No. 6,127,406 A 20001003 CAN 133:281651 AN 2000:699192.

SUMMARY OF THE INVENTION

[0021] The present invention provides new anti-tumor agents which areeffective against a variety of cancer cells. More particularly, thepresent invention relates to certain substituted polyketides whichexhibit a higher degree of selectivity in killing cancer cells. Inaddition, the present invention provides pharmaceutical compositionsuseful in treating tumors comprising a therapeutically effective amountof a certain substituted polyketide. Moreover, the present inventionprovides a method of treating tumors comprising administering to amammal afflicted therewith a therapeutically effective amount of acertain substituted polyketide.

DETAILED DESCRIPTION OF THE INVENTION

[0022] The essence of the instant invention is the discovery thatcertain substituted polyketides are useful in treating tumors. In oneembodiment, the instant invention provides new anti-tumor agents offormula I:

[0023] where

[0024] A is

[0025] —CH═C(R₁)CH₂—,

[0026] —CH₂N(R₂)C(O)—,

[0027] —C(O)N(R₂)CH₂—,

[0028] —CH₂N(R₂)CH₂—,

[0029] —CH₂N(CO₂R₃)CH₂— or

[0030] —CH₂N(COR₂)CH₂—;

[0031] B is —CH(R₁)CH═CHCH═CH₂, —CH(R₂)R₁, —CH(R₁)CH═CHR₂,—CH(R₁)CH═CHC(O)OR₂, —CH(R₁)CH═CHC(O)N(R₁)R₂, —CH(R₁)CH₂OR₂ or Ar;

[0032] C is H, —C(O)N(R₁)R₂, —C(O)NHCH₂(CH₂)_(n)N(CH₃)₂ or—C(O)NHCH₂(CH₂)_(n)-4-morpholino;

[0033] R₁ is H or (C₁)alkyl;

[0034] R₂ is H, (C₁)alkyl, (C₂₋₆)alkenyl, (C₂₋₆)alkynyl, (C₁₋₆)alkyl-Aror Ar;

[0035] R₃ is (C₁)alkyl, (C₁)alkyl-Ar or Ar;

[0036] Ar is an aromatic or heteroaromatic ring selected from

[0037] R₄ and R₅ are, independently, H, (C₁)alkyl, OH, O(C₁₋₆)alkyl,OCH₂(PH₂)_(n)OH, O(CH₂)_(n)CO₂H, OCH₂(CH₂)_(n)N(CH₃)₂,OCH₂(CH₂)_(n)-4-morpholino, F, Cl, Br or CF₃; and

[0038] n is 1 or 2;

[0039] with the proviso that when A is —CH═C(CH₃)CH₂— or —CH═CHCH₂—,

[0040] then either:

[0041] B cannot be —CH(CH₃)CH═CHCH═CH₂, —CH(CH₃)CH₂Ph, —CH(CH₃)Ph,—CH(CH₃)-n-Bu,

[0042] or C cannot be —C(O)N(R₁)R₂ or H;

[0043] or an acid or base addition salt thereof, where possible.

[0044] Preferred compounds are those of formula Ia:

[0045] where

[0046] A′ is

[0047] —CH═C(R₁′)CH₂—,

[0048] —CH₂N(R₂′)C(O)—,

[0049] —C(O)N(R₂′)CH₂—,

[0050] —CH₂N(CO₂R₃′)CH₂— or

[0051] —CH₂N(COR₂′)CH₂—;

[0052] B′ is —CH(R₁′)CH═CHCH═CH₂, —CH(R₂′)R₁′, —CH(R₁′)CH═CHR₂′,—CH(R₁′)CH₂OR₂′ or Ar′;

[0053] C′ is H, —C(O)N(R₁′)R₂′, —C(O)NHCH₂(CH₂)_(n)N(CH₃)₂ or—C(O)NHCH₂(CH₂)_(n)-4-morpholino;

[0054] R₁′ is H or (C₁)alkyl;

[0055] R₂′ is H, (C₁)alkyl, (C₂₋₆)alkenyl, (C₂₋₆)alkynyl, (C₁)alkyl-Ar′or Ar′;

[0056] R₃′ is (C₁)alkyl, (C₁)alkyl-Ar′ or Ar′;

[0057] Ar′ is an aromatic or heteroaromatic ring selected from

[0058] R₄′ and R₅′ are, independently, H, (C₁)alkyl, OH, O(C₁₋₆)alkyl,OCH₂(CH₂)_(n)OH, O(CH₂)_(n)CO₂H, OCH₂(CH₂)_(n)N(CH₃)₂,OCH₂(CH₂)_(n)-4-morpholino, F, Cl, Br or CF₃; and

[0059] n is 1 or 2;

[0060] with the proviso that when A′ is —CH═C(CH₃)CH₂— or —CH═CHCH₂—,

[0061] then either:

[0062] B′ cannot be —CH(CH₃)CH═CHCH═CH₂, —CH(CH₃)CH₂Ph, —CH(CH₃)Ph,—CH(CH₃)-n-Bu,

[0063] or C′ cannot be —C(O)N(R₁′)R₂′ or H;

[0064] or an acid or base addition salt thereof, where possible.

[0065] More preferred compounds are those of formula Ib:

[0066] where

[0067] A″ is

[0068] —CH═C(R₁″)CH₂—,

[0069] —CH₂N(R₂″)C(O)— or

[0070] —C(O)N(R₂″)CH₂—;

[0071] B″ is —CH(R₁″)CH═CHCH═CH₂, —CH(R₂″)R₁″, —CH(R₁″)CH═CHR₂″,—CH(R₁″)CH₂OR₂″ or Ar″;

[0072] C″ is H, —C(O)N(R₁″)R₂″, —C(O)NHCH₂(CH₂)_(r)N(CH₃)₂ or—C(O)NHCH₂(CH₂)_(n)-4-morpholino;

[0073] R₁″ is H or —CH₃;

[0074] R₂″ is H, (C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₂₋₆)alkynyl,(C₁₋₆)alkyl-Ar″ or Ar″;

[0075] Ar″ is an aromatic or heteroaromatic ring selected from

[0076] R₄″ and R₅″ are, independently, H, (Cl)alkyl, OH, O(Cl)alkyl,OCH₂(CH₂)_(n)OH, O(CH₂), CO₂H, OCH₂(CH₂), N(CH₃)₂,OCH₂(CH₂)_(n)-4-morpholino, F, Cl, Br or CF₃, and

[0077] n is 1 or 2;

[0078] with the proviso that when A″ is —CH═C(CH₃)CH₂— or —CH═CHCH₂—,

[0079] then either:

[0080] B″ cannot be —CH(CH₃)CH═CHCH═CH₂, —CH(CH₃)CH₂Ph, —CH(CH₃)Ph,—CH(CH₃)-n-Bu,

[0081] or C″ cannot be —C(O)N(R₁″)R₂″ or H;

[0082] or an acid or base addition salt thereof, where possible.

[0083] Even more preferred compounds are those of formula Ic:

[0084] where

[0085] A′″ is

[0086] —CH═C(R₁′″)CH₂—,

[0087] —CH₂N(R₂′″)C(O)— or

[0088] —C(O)N(R₂′″)CH₂—;

[0089] B′″ is —CH(R₁′″)CH═CHCH═CH₂, —CH(R₂′″)R₁′″, —CH(R₁′″)CH═CHR₂′″,—CH(R₁′″)CH₂OR₂′″ or Ar′″;

[0090] C′″ is H or —C(O)N(R₁′″)R₂′″;

[0091] R₁′″ is H or CH₃;

[0092] R₂′″ is H, (C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₂₋₆)alkynyl,(C₁₋₆)alkyl-Ar′″ or Ar′″;

[0093] Ar′″ is an aromatic ring having the formula

[0094] R₄′″ and R₅′″ are, independently, H, (C₁)alkyl, OH, O(C₁₋₆)alkyl,F, Cl, Br or CF₃;

[0095] with the proviso that when A′″ is —CH═C(CH₃)CH₂— or —CH═CHCH₂—,

[0096] then either:

[0097] B′″ cannot be —CH(CH₃)CH═CHCH═CH₂, —CH(CH₃)CH₂Ph, —CH(CH₃)Ph,—CH(CH₃)-n-Bu,

[0098] or C′″ cannot be —C(O)N(R₁′″)R₂′″ or H;

[0099] or an acid or base addition salt thereof, where possible.

[0100] In another embodiment, the instant invention providespharmaceutical compositions useful in treating tumors comprising apharmaceutically acceptable carrier or diluent and a therapeuticallyeffective amount of a compound of formula I above, or a pharmaceuticallyacceptable acid or base addition salt thereof, where possible,preferably a compound of formula Ia above, or a pharmaceuticallyacceptable acid or base addition salt thereof, where possible, morepreferably a compound of formula Ib above, or a pharmaceuticallyacceptable acid or base salt thereof, where possible, and even morepreferably a compound of formula Ic above, or a pharmaceuticallyacceptable acid or base addition salt thereof, where possible.

[0101] In still another embodiment, the instant invention provides amethod for treating tumors comprising administering to a mammal in needof such treatment a therapeutically effective amount of a compound offormula I above, or a pharmaceutically acceptable acid or base additionsalt thereof, where possible, preferably a compound of formula Ia above,or a pharmaceutically acceptable acid or base addition salt thereof,where possible, more preferably a compound of formula Ib above, or apharmaceutically acceptable acid or base addition salt thereof, wherepossible, and even more preferably a compound of formula Ic above, or apharmaceutically acceptable acid or base addition salt thereof, wherepossible.

[0102] In the above definitions: 1) the alkyl groups containing 1 to 6carbon atoms are either straight or branched chain or cycloalkane, ofwhich examples include isopropyl, isobutyl, t-butyl, isopentyl,neopentyl, isohexyl, 3-methylpentyl, 2,2-dimethylbutyl,2,3-dimethylbutyl, 1,1,2,2-tetramethylethyl, cyclopentyl and cyclohexyl.

[0103] Although the pharmaceutically acceptable acid or base additionsalts are preferred, it should be understood that all of the acid orbase addition salts of the compounds of formula I are intended to beincluded within the scope of the present invention.

[0104] The acid addition salts of the compounds of formula I may bethose of pharmaceutically acceptable organic or inorganic acids.Although the preferred acid addition salts are those of hydrochloric andmethanesulfonic acid, salts of sulfuric, phosphoric, citric, fumaric,maleic, benzoic, benzenesulfonic, succinic, tartaric, lactic and aceticacid may also be utilized.

[0105] Likewise, the base addition salts of the compounds of formula Imay be those of pharmaceutically acceptable organic or inorganic bases.Preferred base addition salts are those derived from pharmaceuticallyacceptable inorganic bases, more preferably ammonium hydroxide or analkali or alkaline earth metal hydroxide, e.g, lithium hydroxide, sodiumhydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxideand manganese hydroxide.

[0106] The substituted polyketides of formula I may be prepared asdepicted below. In the event that the groups A-F contain free hydroxygroups, then the asterisk designation (e.g., A*) indicates that thosegroups are protected with acid labile protecting groups (e.g., TBS). Allacid labile protecting groups covered by the asterisk are removed in thefinal step (HCl).

[0107] As to the individual steps in Scheme 1, Step A involves theaddition of a ketone of formula 2 to an aldehyde of formula 1 to obtaina hydroxyketone of formula 3. The addition requires between 1 and 20equivalents of 2 relative to aldehyde 1, preferably between 5 and 15equivalents of 2 relative to aldehyde 1. The coupling is conducted inthe presence of: 1) a dialkylboron halide or triflate, preferably achiral boron chloride or triflate, more preferablyB-chlorodiisopinocampheylborane; 2) a base, preferably an amine, morepreferably triethylamine; and 3) a polar organic solvent, preferably anether, more preferably diethyl ether, at a temperature of between −100°C. and 20° C., preferably between −78° C. and −20° C., for a period ofbetween 2 and 72 hours, preferably for 16 hours.

[0108] Step B concerns the reduction of the hydroxyketone of formula 3,to obtain a 1,3-diol compound of formula 4. The reduction is conductedin the presence of: 1) a ketone reducing agent, preferably a borohydridesuch as tetramethylammonium triacetoxyborohydride; 2) a polar organicsolvent, preferably acetonitrile; and 3) a protic solvent, preferably acarboxylic acid, such as acetic acid, at a temperature of between −78°C. and 20° C., preferably between −40° C. and −10° C., for a period ofbetween 2 and 72 hours, preferably for 16 hours.

[0109] Step C concerns the hydrolysis and cyclization of the 1,3-diolcompound 4 to a substituted polyketide of formula 5. The hydrolysisreaction is conducted in the presence of: 1) a protic acid, preferablyan aqueous protic acid solution, preferably an aqueous hydrogen halidesolution, such as aqueous hydrogen chloride; and 2) a polar organicsolvent, preferably a mixture of polar organic solvents, preferably amixture of an aliphatic alcohol and an ether, such as methanol andtetrahydrofuran, at a temperature of between −20° C. and 40° C.,preferably between 20° C. and 25° C., for a period of 8 hours and 7days, preferably between 16 and 72 hours, more preferably between 24 and48 hours.

[0110] As to the individual steps in Scheme 2, Step A involves theoxidative hydrolysis of a para-methoxybenzyl ether of formula 1 to adiol of formula 2. The oxidative hydrolysis is conducted in the presenceof: 1) an oxidant, preferably a quinone such as2,3-dichloro-5,6-dicyano-1,4-benzoquinone; 2) water; and 3) a polarorganic solvent, preferably a halogenated hydrocarbon such as methylenechloride, at a temperature of between −20° C. and 40° C., preferably at25° C., for a period of between 1 hour and 72 hours, preferably for 1hour.

[0111] Step B involves the oxidation of an alcohol of formula 2 toobtain an aldehyde of formula 3. The oxidation is conducted in thepresence of: 1) an oxidizing reagent, preferably a mild oxidizingreagent such as the combinations of oxalyl chloride, DMSO andtriethylamine; sulfur trioxide-pyridine complex, DMSO and triethylamine;and 2,2,6,6-tetramethyl-1-piperidinyloxy free radical anddiacetoxyiodobenzene; and 2) an inert organic solvent, preferably apolar organic solvent such as methylene chloride, at a temperature ofbetween −78° C. and 40° C., preferably from −20° C. to 25° C., for aperiod of between 10 minutes and 48 hours, preferably for 3 hours.

[0112] Step C involves the olefination of an aldehyde of formula 3 withan olefinating reagent, preferably (CF₃CH₂O)₂P(O)CH₂CO₂CH₃, to obtain anolefin of formula 4. The olefination is conducted in the presence of: 1)a strong base, preferably an alkali metal salt such as potassiumhexamethyldisilazide or butyllithium; and 2) an inert organic solvent,preferably a hydrocarbon such as toluene, or an ether such astetrahydrofuran, at a temperature of between −78° C. and 25° C.,preferably at 0° C., for a period of between 10 minutes and 48 hours,preferably for 3 hours.

[0113] Step D concerns the carbamoylation of the olefin of formula 4with an isocyanate either of formula C*NCO or Cl₃C(O)NCO to give acarbamate of formula 5. In the case of using C*NCO, the carbamoylationis conducted in the presence of a Lewis acid such as Bu₂Sn(OAc)₂ or aweak base such as triethylamine, in a polar aprotic solvent, preferablya halogenated solvent such as methylene chloride at a temperature ofbetween −20° C. and 100° C., preferably between 0° C. and 50° C., for aperiod of between 5 minutes and 72 hours, preferably between 1 hour and24 hours. In the case using Cl₃C(O)NCO, which produces substitutedpolyketides of formula I where C═H, the carbamoylation is conducted inthe presence of a polar aprotic solvent, preferably a halogenatedsolvent such as methylene chloride, at a temperature of between −20° C.and 100° C., preferably at 25° C., for a period of between 5 minutes and72 hours, preferably between 1 hour and 8 hours; the work-up of thisstep is conducted in the presence of a protic organic solvent,preferably an alcohol such as methanol, in the presence of a base, forexample, a carbonate such as potassium carbonate, at a temperature ofbetween between 0° C. and 100° C., preferably at 25° C., for a period ofbetween 5 minutes and 72 hours, preferably between 1 hour and 8 hours.

[0114] Step E involves the reduction of a carbamate of formula 5 toobtain an alcohol of formula 6. The reduction is conducted in thepresence of: 1) a reducing reagent, preferably an aluminum hydridereagent such as diisobutylaluminum hydride; and 2) an inert organicsolvent, preferably a polar organic solvent such as methylene chloride,at a temperature of between −100° C. and 0° C., preferably at −78° C.,for a period of between 10 minutes and 48 hours, preferably for 2 hours.

[0115] Step F involves the oxidation of an alcohol of formula 6 toobtain an aldehyde of formula 7. The oxidation is conducted in thepresence of: 1) an oxidizing reagent, preferably a mild oxidizingreagent such as the Dess-Martin periodinane reagent; or the combinationsof oxalyl chloride, DMSO and triethylamine; sulfur trioxide-pyridinecomplex, DMSO and triethylamine; and2,2,6,6-tetramethyl-1-piperidinyloxy free radical anddiacetoxyiodobenzene; and 2) an inert organic solvent, preferably apolar organic solvent such as methylene chloride, at a temperature ofbetween −78° C. and 40° C., preferably from −20° C. to 25° C., for aperiod of between 10 minutes and 48 hours, preferably for a period ofbetween 1 and 3 hours.

[0116] As to the individual steps in Scheme 3, Step A involves thereduction of a cyclic para-methoxyphenyl acetal of formula 1 to obtainan alcohol of formula 2. The reduction is conducted in the presenceof: 1) a metal hydride, preferably an aluminum hydride such asdiisobutylaluminum hydride; and 2) an aprotic organic solvent,preferably an ether such as tetrahydrofuran, at a temperature of between−100° C. and 10° C., preferably from −78° C. to 0° C., for a period ofbetween 10 minutes and 8 hours, preferably for 2 hours.

[0117] Step B involves the etherification of an alcohol of formula 2 toobtain an ether of formula 3. The etherification is conducted in thepresence of: 1) an alcohol of formula R₂*OH, where R₂* is as describedabove; 2) a coupling reagent such as diethyl azodicarboxylate; 3) aphosphine such as triphenylphosphine; and 4) a polar organic solvent,such tetrahydrofuran, at a temperature of between −78° C. and 60° C.,preferably between −20° C. and 40° C., for a period of between 2 and 72hours, preferably for 16 hours. Alternatively, R₂*OH is replaced with anR₂*halide or R₂*sulfonate. In this case, the etherification is conductedin the presence of: 1) a base, preferably an alkali metal base, such assodium hydride; 2) a polar organic solvent, such asN,N-dimethylformamide; and 3) an optional catalytic amount of an iodidesalt, such as potassium iodide, at a temperature of between −78° C. and60° C., preferably between −20° C. and 40° C., for a period of between 2and 72 hours, preferably for 16 hours.

[0118] Step C involves the oxidative hydrolysis of an ether of formula 3to a diol of formula 4. The oxidative hydrolysis is conducted in thepresence of: 1) an oxidant, preferably a quinone such as2,3-dichloro-5,6-dicyano-1,4-benzoquinone; 2) water; and 3) a polarorganic solvent, preferably a halogenated hydrocarbon such as methylenechloride, at a temperature of between −20° C. and 40° C., preferably at25° C., for a period of between 1 hour and 72 hours, preferably for 1hour.

[0119] As to the individual steps in Scheme 4, Step A involves thepalladium-mediated coupling of an alkyl iodide of formula 1 and a vinyliodide of formula 2 to obtain an alkene of formula 3. Thepalladium-mediated coupling is conducted in the presence of: 1) ahindered organometallic reagent, preferably a hindered organolithiumreagent such as t-butyllithium; 2) either a zinc halide such as zincchloride or a hindered boron reagent such as9-methoxy-9-borabicyclo[3.3.1]nonane; 3) a palladium reagent such astetrakis(triphenylphosphine)palladium(0) or[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II); and 4) apolar organic solvent, preferably an ether such as diethyl ether, at atemperature of between −78° C. and 25° C., for a period of between 1hour and 72 hours.

[0120] Step B involves the oxidative hydrolysis of an alkene of formula3 to a diol of formula 4. The oxidative hydrolysis is conducted in thepresence of: 1) an oxidant, preferably a quinone such as2,3-dichloro-5,6-dicyano-1,4-benzoquinone; 2) water; and 3) a polarorganic solvent, preferably a halogenated hydrocarbon such as methylenechloride, at a temperature of between −20° C. and 40° C., preferably at25° C., for a period of between 1 hour and 72 hours, preferably for 1hour.

[0121] As to the individual steps in Scheme 5, Step A involves theolefination of an aldehyde of formula 2 with a phosphonium salt offormula 1 to obtain an alkene of formula 3. The olefination is conductedin the presence of: 1) a strong base, preferably an alkali metal saltsuch as potassium hexamethyldisilazide or butyllithium; and 2) an inertorganic solvent, preferably a hydrocarbon such as toluene, or an ethersuch as tetrahydrofuran, at a temperature of between −78° C. and 25° C.,preferably at 0° C., for a period of between 10 minutes and 48 hours,preferably for 3 hours.

[0122] Step B involves the oxidative hydrolysis of an alkene of formula3 to a diol of formula 4. The oxidative hydrolysis is conducted in thepresence of: 1) an oxidant, preferably a quinone such as2,3-dichloro-5,6-dicyano-1,4-benzoquinone; 2) water; and 3) a polarorganic solvent, preferably a halogenated hydrocarbon such as methylenechloride, at a temperature of between −20° C. and 40° C., preferably at25° C., for a period of between 1 hour and 72 hours, preferably for 1hour.

[0123] As to the individual steps in Scheme 6, Step A involves thereductive amination of an aldehyde of formula 1 to obtain an amine offormula 2. The reductive amination is conducted in the presence of: 1)an amine of formula R₅NH₂ where R₅ is as defined above; 2) a reducingagent, preferably a hydride, more preferably a borohydride salt such assodium borohydride; and 3) a polar organic solvent, preferably a proticorganic solvent such as ethanol, at a temperature of between 0° C. and40° C., preferably from 5° C. to 25° C., for a period of between 10minutes and 48 hours, preferably for 16 hours.

[0124] Step B involves the acylation of an amine of formula 2 to obtainan amide of formula 4. The acylation is conducted in the presence of: 1)a carboxylic acid of formula 3; 2) a carboxylic acid coupling reagent,preferably a diimide such as1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and asuitable activating agent common to diimide coupling reactions, such as1-hydroxybenzotriazole; and 3) a polar organic solvent, preferably a lowmolecular weight amide such as DMF, at a temperature of between 0° C.and 40° C., preferably at 25° C., for a period of between 1 and 24hours.

[0125] Step C involves the oxidative hydrolysis of an amide of formula 4to a diol of formula 5. The oxidative hydrolysis is conducted in thepresence of: 1) an oxidant, preferably a quinone such as2,3-dichloro-5,6-dicyano-1,4-benzoquinone; 2) water; and 3) a polarorganic solvent, preferably a halogenated hydrocarbon such as methylenechloride, at a temperature of between −20° C. and 40° C., preferably at25° C., for a period of between 1 hour and 72 hours, preferably for 1hour.

[0126] As to the individual steps in Scheme 7, Step A involves theoxidation of an aldehyde of formula 1 to obtain a carboxylic acid offormula 2. The oxidation is conducted in the presence of: 1) anoxidizing agent such as sodium chlorite; 2) a phosphate salt, preferablysodium dihydrogenphosphate; 3) a protic organic solvent, preferably analcohol such as t-butanol; and 4) an alkene, preferably 2-methylpropene,at a temperature of between 0° C. and 40° C., preferably at 25° C., fora period of between 10 minutes and 8 hours, preferably for 1 hour.

[0127] Step B involves the acylation of an amine of formula 3 to obtainan amide of formula 4. The acylation is conducted in the presence of: 1)a carboxylic acid of formula 2; 2) a carboxylic acid coupling reagent,preferably a diimide such as1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and asuitable activating agent common to diimide coupling reactions, such as1-hydroxybenzotriazole; and 3) a polar organic solvent, preferably a lowmolcular weight amide such as DMF, at a temperature of between 0° C. and40° C., preferably at 25° C., for a period of between 1 and 24 hours.

[0128] Step C involves the oxidative hydrolysis of an amide of formula 4to a diol of formula 5. The oxidative hydrolysis is conducted in thepresence of: 1) an oxidant, preferably a quinone such as2,3-dichloro-5,6-dicyano-1,4-benzoquinone; 2) water; and 3) a polarorganic solvent, preferably a halogenated hydrocarbon such as methylenechloride, at a temperature of between −20° C. and 40° C., preferably at25° C., for a period of between 1 hour and 72 hours, preferably for 1hour.

[0129] As to the individual steps in Scheme 8, Step A involves thereductive amination of an aldehyde of formula 1 to obtain an amine offormula 3. The reductive amination is conducted in the presence of: 1)an amine of formula 2; 2) a reducing agent, preferably a hydride, morepreferably a borohydride salt such as sodium borohydride; and 3) a polarorganic solvent, preferably a lower alkanol such as ethanol, at atemperature of between 0° C. and 40° C., preferably from 5° C. to 25°C., for a period of between 10 minutes and 48 hours, preferably for 16hours.

[0130] Step B involves the acylation of an amine of formula 3 to obtainan amide of formula 4. The acylation is conducted in the presence of: 1)a carboxylic acid of formula R₂*CO₂H where R₂* is defined above; 2) acarboxylic acid coupling reagent, preferably a diimide such as1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and asuitable activating agent common to diimide coupling reactions, such as1-hydroxybenzotriazole; and 3) a polar organic solvent, preferably a lowmolcular weight amide such as DMF, at a temperature of between 0° C. and40° C., preferably at 25° C., for a period of between 1 and 24 hours.

[0131] Step C involves the oxidative hydrolysis of an amide of formula 4to a diol of formula 5. The oxidative hydrolysis is conducted in thepresence of: 1) an oxidant, preferably a quinone such as2,3-dichloro-5,6-dicyano-1,4-benzoquinone; 2) water; and 3) a polarorganic solvent, preferably a halogenated hydrocarbon such as methylenechloride, at a temperature of between −20° C. and 40° C., preferably at25° C., for a period of between 1 hour and 72 hours, preferably for 1hour.

[0132] As to the individual steps in Scheme 9, Step A involves theacylation of an amine of formula 1 to obtain a carbamate of formula 2.The acylation is conducted in the presence of: 1) a chloroformate offormula ClCO₂R₃* where R₃* is defined above; 2) a weak base, preferablyan amine such as triethylamine; and 3) a polar organic solvent,preferably a halogenated hydrocarbon such as methylene chloride, at atemperature of between −78° C. and 40° C., preferably at 5° C., for aperiod of between 1 and 24 hours.

[0133] Step B involves the oxidative hydrolysis of a carbamate offormula 2 to a diol of formula 3. The oxidative hydrolysis is conductedin the presence of: 1) an oxidant, preferably a quinone such as2,3-dichloro-5,6-dicyano-1,4-benzoquinone; 2) water; and 3) a polarorganic solvent, preferably a halogenated hydrocarbon such as methylenechloride, at a temperature of between −20° C. and 40° C., preferably at25° C., for a period of between 1 hour and 72 hours, preferably for 1hour.

[0134] As to the individual steps in Scheme 10, Step A involves theolefination of an aldehyde of formula 1 with a phosphonium salt offormula 2 to obtain an alkene of formula 3. The olefination is conductedin the presence of: 1) a strong base, preferably an alkali metal saltsuch as potassium hexamethyldisilazide or butyllithium; and 2) an inertorganic solvent, preferably a hydrocarbon such as toluene, or an ethersuch as tetrahydrofuran, at a temperature of between −78° C. and 25° C.,preferably at 0° C., for a period of between 10 minutes and 48 hours,preferably for 3 hours.

[0135] Step B involves the oxidative hydrolysis of an alkene of formula3 to a diol of formula 4. The oxidative hydrolysis is conducted in thepresence of: 1) an oxidant, preferably a quinone such as2,3-dichloro-5,6-dicyano-1,4-benzoquinone; 2) water; and 3) a polarorganic solvent, preferably a halogenated hydrocarbon such as methylenechloride, at a temperature of between −20° C. and 40° C., preferably at25° C., for a period of between 1 hour and 72 hours, preferably for 1hour.

[0136] As to the individual steps in Scheme 11, Step A involves theolefination of an aldehyde of formula 1 with a phosphonate of formula 2to obtain an olefin of formula 3. The olefination is conducted in thepresence of: 1) a strong base, preferably a potassium salt such aspotassium hexamethyldisilazide; 2) a crown ether such as 18-crown-6; and3) an inert organic solvent, preferably a hydrocarbon such as toluene,at a temperature of between −78° C. and 25° C., preferably at 0° C., fora period of between 10 minutes and 48 hours, preferably for 3 hours.

[0137] Step B involves the oxidative hydrolysis of an alkene of formula3 to a diol of formula 4. The oxidative hydrolysis is conducted in thepresence of: 1) an oxidant, preferably a quinone such as2,3-dichloro-5,6-dicyano-1,4-benzoquinone; 2) water; and 3) a polarorganic solvent, preferably a halogenated hydrocarbon such as methylenechloride, at a temperature of between −20° C. and 40° C., preferably at25° C., for a period of between 1 hour and 72 hours, preferably for 1hour.

[0138] As to the individual steps in Scheme 12, Step A involves theolefination of an aldehyde of formula 1 with a phosphonate of formula 2to obtain an olefin of formula 3. The olefination is conducted in thepresence of: 1) a strong base, preferably a potassium salt such aspotassium hexamethyldisilazide; 2) a crown ether such as 18-crown-6; and3) an inert organic solvent, preferably a hydrocarbon such as toluene,at a temperature of between −78° C. and 25° C., preferably at 0° C., fora period of between 10 minutes and 48 hours, preferably for 3 hours.

[0139] Step B involves the oxidative hydrolysis of an alkene of formula3 to a diol of formula 4. The oxidative hydrolysis is conducted in thepresence of: 1) an oxidant, preferably a quinone such as2,3-dichloro-5,6-dicyano-1,4-benzoquinone; 2) water; and 3) a polarorganic solvent, preferably a halogenated hydrocarbon such as methylenechloride, at a temperature of between −20° C. and 40° C., preferably at25° C., for a period of between 1 hour and 72 hours, preferably for 1hour.

[0140] The syntheses described in Scheme 13 may be applied when B* isnot —CH(R₁)CH═CH—CH═CH₂ or —CH(R₁)CH═CH₂. As to the individual steps inScheme 13, Step A involves the addition of a butene group to an aldehydeof formula 1 to obtain an alcohol of formula 2. The addition isconducted in the presence of: 1) a crotylboron reagent, preferably achiral crotylboron reagent, more preferably a Z-crotylboronate derivedfrom diisopropyl tartrate; 2) an optional drying reagent such asmolcular sieves; and 3) an inert organic solvent, preferably ahydrocarbon such as toluene, at a temperature of between −100° C. and 5°C., preferably at −78° C., for a period of between 10 minutes and 48hours, preferably for 3 hours.

[0141] Step B involves the alkylation of an alcohol of formula 2 toobtain an alcohol of formula 3. The alkylation is conducted in thepresence of: 1) a reactive benzylating reagent, preferably a reactivepara-methoxybenzylating reagent such asp-methoxybenzyl-2,2,2-trichloroacetimidate; 2) a proton source,preferably a sulfonic acid such as pyridinium p-toluenesulfonate; and 3)a polar organic solvent, preferably a halogenated hydrocarbon such asmethylene chloride, at a temperature of between −78° C. and 25° C.,preferably at 0° C., for a period of between 10 minutes and 48 hours,preferably for 3 hours.

[0142] Step C involves the two stage oxidative cleavage of an alcohol offormula 3 to obtain an aldehyde of formula 4. The first stage of theoxidative cleavage is conducted in the presence of: 1) a dihydroxylatingreagent, preferably an osmium reagent such as osmium tetroxide; 2) acooxidant such as N-morpholine-N-oxide; and 3) a mixture of aproticpolar and protic solvents such as a mixture of acetone, water, andt-butanol, at a temperature of between −20° C. and 40° C., preferably at25° C., for a period of between 10 minutes and 48 hours, preferably for3 hours. The second stage of the oxidative cleavage is conducted in thepresence of: 1) a periodate salt such as sodium periodate; and 2) amixture of aprotic polar and protic solvents such as a mixture oftetrahydrofuran and water, at a temperature of between −20° C. and 40°C., preferably at 25° C., for a period of between 10 minutes and 48hours, preferably for 3 hours.

[0143] Step D involves the addition of a butene group to an aldehyde offormula 4 to obtain an alcohol of formula 5. The addition is conductedin the presence of: 1) a crotyl addition reagent, preferably a crotyltinreagent such as crotyltributyltin; 2) a Lewis acid such asborontrifluoride etherate; and 3) an inert organic solvent, preferably ahalogenated hydrocarbon such as methylene chloride, at a temperature ofbetween −100° C. and 5° C., preferably at −78° C., for a period ofbetween 10 minutes and 48 hours, preferably for 2 hours.

[0144] Step E involves the silylation of an alcohol of formula 5 toobtain a silyl ether of formula 6. The silylation is conducted in thepresence of: 1) a silylating reagent, preferably at-butyldimethylsilylating reagent such as t-butyldimethylsilyltriflate;2) a weak base, preferably a nitrogen-containing base, more preferably apyridine base such as 2,6-lutidine; and 3) an inert organic solvent,preferably a halogenated hydrocarbon such as methylene chloride, at atemperature of between −100° C. and 5° C., preferably at −20° C., for aperiod of between 10 minutes and 48 hours, preferably for 2 hours.

[0145] The syntheses described in Scheme 14 may be applied when B* isnot —CH(R₁)CH═CH—CH═CH₂ or —CH(R₁)CH═CH₂. As to the individual steps inScheme 14, Step A involves the two stage oxidative cleavage of an alkeneof formula 1 to obtain an aldehyde of formula 2. The first stage of theoxidative cleavage is conducted in the presence of: 1) a dihydroxylatingreagent, preferably an osmium reagent such as osmium tetroxide; 2) acooxidant such as N-morpholine-N-oxide; and 3) a mixture of aproticpolar and protic solvents such as a mixture of acetone, water, andt-butanol, at a temperature of between −20° C. and 40° C., preferably at25° C., for a period of between 10 minutes and 48 hours, preferably for3 hours. The second stage of the oxidative cleavage is conducted in thepresence of: 1) a periodate salt such as sodium periodate; and 2) amixture of aprotic polar and protic solvents such as a mixture oftetrahydrofuran and water, at a temperature of between −20° C. and 40°C., preferably at 25° C., for a period of between 10 minutes and 48hours, preferably for 3 hours.

[0146] Step B involves the reduction of an aldehyde of formula 2 toobtain an alcohol of formula 3. The reduction is conducted in thepresence of: 1) a hydride reducing agent, preferably an aluminum hydridesuch as lithium aluminum hydride or diisobutylaluminum hydride, or aborohydride such as sodium borohydride; and 2) a polar organic solvent,preferably an ether such as tetrahydrofuran, at a temperature of between−100° C. and 40° C., preferably from −20° C. to 25° C., for a period ofbetween 10 minutes and 48 hours, preferably for 2 hours.

[0147] Step C involves the iodination of an alcohol of formula 3 toobtain an iodide of formula 4. The iodination is conducted in thepresence of: 1) an iodinating reagent such as 12; 2) aphosphorus-containing compound such as triphenylphoshine; 3) a weakbase, preferably a weak nitrogen-containing base such as imidazole; and4) a polar organic solvent, preferably an ester such as ethyl acetate,at a temperature of between −10° C. and 40° C., preferably at 25° C.,for a period of between 10 minutes and 48 hours, preferably for 2 hours.Step D involves the two stage hydroxylation of an alkene of formula 1 toobtain an alcohol of formula 5. The first stage of the hydroxylation isconducted in the presence of: 1) a borane such as9-borabicyclo[3.3.1]nonane; and 2) a polar organic solvent, preferablyan ether such as tetrahydrofuran, at a temperature of between −10° C.and 40° C., preferably at 0° C., for a period of between 1 hour and 48hours, preferably for 24 hours. The second stage of the hydroxylation isconducted in the presence of: 1) an oxidant, preferably a peroxide suchas hydrogen peroxide; 2) a strong alkali base, preferably a hydroxidebase such as sodium hydroxide; and 3) a polar organic solvent,preferably an ether such as tetrahydrofuran, at a temperature of between−10° C. and 40° C., preferably at 0° C., for a period of between 10minutes and 8 hours, preferably for 1 hour.

[0148] Step E involves the iodination of an alcohol of formula 5 toobtain an iodide of formula 6. The iodination is conducted in thepresence of: 1) an iodinating reagent such as 12; 2) aphosphorus-containing compound such as triphenylphoshine; 3) a weakbase, preferably a weak nitrogen-containing base such as imidazole; and4) a polar organic solvent, preferably an ester such as ethyl acetate,at a temperature of between −10° C. and 40° C., preferably at 25° C.,for a period of between 10 minutes and 48 hours, preferably for 2 hours.

[0149] Step F involves the two stage iodination of an alkene of formula1 to obtain an iodide of formula 6. The first stage of the iodination isconducted in the presence of: 1) a borane such as9-borabicyclo[3.3.1]nonane; and 2) a polar organic solvent, preferablyan ether such as tetrahydrofuran, at a temperature of between −10° C.and 40° C., preferably at 0° C., for a period of between 1 hour and 48hours, preferably for 24 hours. The second stage of the iodination isconducted in the presence of 12; and 2) a polar organic solvent,preferably an ether such as tetrahydrofuran, at a temperature of between−10° C. and 40° C., preferably at 0° C., for a period of between 10minutes and 8 hours.

[0150] Step G involves the phoshine addition reaction of an iodide offormula 6 to obtain a phosphonium iodide salt of formula 7. The phoshineaddition reaction is conducted in the presence of: 1) a phosphorusreagent such as triphenylphosphine; 2) a base, preferably an amine basesuch as diisopropylethylamine; and 3) an organic solvent, preferably apolar aprotic solvent such as acetonitrile, at a temperature of between25° C. and 150° C., preferably at 90° C., for a period of between 1 hourand 72 hours, preferably for 18 hours.

[0151] As to the individual steps in Scheme 15, Step A involves thealkylation of an alcohol of formula 1 to obtain an ether of formula 2.The alkylation is conducted in the presence of: 1) a reactivebenzylating reagent, preferably a reactive para-methoxybenzylatingreagent such as p-methoxybenzyl-2,2,2trichloroacetimidate; 2) a protonsource, preferably a sulfonic acid such as pyridiniump-toluenesulfonate; and 3) a polar organic solvent, preferably ahalogenated hydrocarbon such as methylene chloride, at a temperature ofbetween −78° C. and 25° C., preferably at 0° C., for a period of between10 minutes and 48 hours, preferably for 3 hours.

[0152] Step B involves the reduction of an ether of formula 2 to obtainan alcohol of formula 3. The reduction is conducted in the presenceof: 1) a metal hydride, preferably an aluminum hydride such as lithiumaluminum hydride or diisobutylaluminum hydride; and 2) a polar organicsolvent, preferably an ether such as tetrahydrofuran, at a temperatureof between

[0153] 100° C. and 10° C., preferably from −78° C. to 0° C., for aperiod of between 10 minutes and 8 hours, preferably for 2 hours.

[0154] Step C involves the alkylation of an alcohol of formula 3 toobtain an ether of formula 4. The alkylation is conducted in thepresence of: 1) an alcohol of formula A*OH, where A* is as describedabove; 2) a coupling reagent such as diethyl azodicarboxylate; 3) aphosphine such as triphenylphosphine; and 4) a polar organic solvent,such tetrahydrofuran, at a temperature of between −78° C. and 60° C.,preferably between −20° C. and 40° C., for a period of between 2 and 72hours, preferably for 16 hours.

[0155] Step D involves the oxidative hydrolysis of an ether of formula 4to an alcohol of formula 5. The oxidative hydrolysis is conducted in thepresence of: 1) an oxidant, preferably a quinone such as2,3-dichloro-5,6-dicyano-1,4-benzoquinone; 2) water; and 3) a polarorganic solvent, preferably a halogenated hydrocarbon such as methylenechloride, at a temperature of between −20° C. and 40° C., preferably at25° C., for a period of between 1 hour and 72 hours, preferably for 1hour.

[0156] Step E involves the oxidation of an alcohol of formula 5 toobtain an aldehyde of formula 6. The oxidation is conducted in thepresence of: 1) an oxidizing reagent, preferably a mild oxidizingreagent such as the combinations of oxalyl chloride, DMSO andtriethylamine; sulfur trioxide-pyridine complex, DMSO and triethylamine;and 2,2,6,6-tetramethyl-1-piperidinyloxy free radical anddiacetoxyiodobenzene; and 2) an inert organic solvent, preferably apolar organic solvent such as methylene chloride, at a temperature ofbetween −78° C. and 40° C., preferably from −20° C. to 25° C., for aperiod of between 10 minutes and 48 hours, preferably for 3 hours.

[0157] As to the individual steps in Scheme 16, Step A involves thepalladium-mediated coupling of an alkyl zinc bromide of formula 1 and avinyl iodide of formula 2 to obtain an alkene of formula 3. Thepalladium-mediated coupling is conducted in the presence of: 1) apalladium reagent such as tetrakis(triphenylphosphine)palladium(0); and2) a polar organic solvent, preferably an ether such as diethyl ether ortetrahydrofuran, at a temperature of between −78° C. and 25° C., for aperiod of between 1 hour and 72 hours.

[0158] Step B involves the amidation of an alkene of formula 3 to obtainan amide of formula 4. The amidation is conducted in the presence of: 1)an O,N-dialkylated hydroxylamine such as N,N-dimethylhydroxylaminehydrochloride; 2) an organometallic reagent, preferably analkylmagnesium halide or a trialkylaluminum reagent such astrimethylaluminum; and 3) an organic solvent, preferably a hydrocarbonsuch as toluene or hexane, or a mixture of the two, at a temperature ofbetween −20° C. and 40° C., preferably at 25° C., for a period ofbetween 1 hour and 72 hours, preferably for 1 hour.

[0159] Step C involves the addition reaction of an amide of formula 4with a metalloalkane, preferably an alkyllithium or alkylmagnesiumhalide reagent such as ethylmagnesium bromide, to obtain a ketone offormula 5. The addition reaction is conducted in the presence of a polarorganic solvent such as tetrahydrofuran, at a temperature of between−100° C. and 0° C., preferably at −78° C., for a period of between 1hour and 72 hours, preferably for 4 hours.

[0160] Step D involves the addition reaction of a ketone of formula 5with an aldehyde of formula B*CHO, where B is as described above, toobtain a hydroxyketone of formula 6. The addition reaction is conductedin the presence of: 1) a Lewis acid, preferably a boron or titaniumreagent such as trisopropoxytitanium chloride; and 2) a polar organicsolvent, preferably an ether such as diethyl ether or tetrahydrofuran,at a temperature of between −100° C. and 0° C., preferably at −78° C.,for a period of between 1 hour and 72 hours, preferably for 16 hours.

[0161] Step E involves the alkylation of a hydroxyketone of formula 6 toobtain an ether of formula 7. The alkylation is conducted in thepresence of: 1) a reactive benzylating reagent, preferably a reactivepara-methoxybenzylating reagent such asp-methoxybenzyl-2,2,2-trichloroacetimidate; 2) a proton source,preferably a sulfonic acid such as pyridinium p-toluenesulfonate; and 3)a polar organic solvent, preferably a halogenated hydrocarbon such asmethylene chloride, at a temperature of between −78° C. and 25° C.,preferably at 0° C., for a period of between 10 minutes and 48 hours,preferably for 3 hours.

[0162] Step F involves the reduction of an ether of formula 7 to obtainan alcohol of formula 8. The reduction is conducted in the presenceof: 1) a reducing agent, preferably an aluminum hydride or borohydride,such as lithium tri-t-butoxyaluminum hydride; 2) a polar organicsolvent, preferably an ether such as diethyl ether or tetrahydrofuran,at a temperature of between −100° C. and 0° C., preferably at −78° C.,for a period of between 1 hour and 72 hours, preferably for 16 hours.

[0163] Step G involves the silylation of an alcohol of formula 8 toobtain an ether of formula 9. The silylation is conducted in thepresence of: 1) a silylating reagent, preferably at-butyldimethylsilylating reagent such as t-butyldimethylsilyltriflate;2) a weak base, preferably a nitrogen-containing base, more preferably apyridine base such as 2,6-lutidine; and 3) an inert organic solvent,preferably a halogenated hydrocarbon such as methylene chloride, at atemperature of between −100° C. and 5° C., preferably at −20° C., for aperiod of between 10 minutes and 48 hours, preferably for 2 hours.

[0164] As to the individual steps in Scheme 17, Step A concerns thecarbamoylation of the olefin of formula 1 with a an isocyanate either offormula C*NCO or Cl₃C(O)NCO to give a carbamate of formula 2. In thecase of using C*NCO, the carbamoylation is conducted in the presence ofa Lewis acid such as Bu₂Sn(OAc)₂ or a weak base such as triethylamine,in a polar aprotic solvent, preferably a halogenated solvent such asmethylene chloride at a temperature of between −20° C. and 100° C.,preferably between 0° C. and 50° C., for a period of between 5 minutesand 72 hours, preferably between 1 hour and 24 hours. In the case usingCl₃C(O)NCO, which produces substituted polyketides of formula I whereC═H, the carbamoylation is conducted in the presence of a polar aproticsolvent, preferably a halogenated solvent such as methylene chloride ata temperature of between −20° C. and 100° C., preferably at 25° C., fora period of between 5 minutes and 72 hours, preferably between 1 hourand 8 hours; the work-up of this step is conducted in the presence of aprotic organic solvent, preferably an alcohol such as methanol, in thepresence of a base, for example, a carbonate such as potassiumcarbonate, at a temperature of between between 0° C. and 100° C.,preferably at 25° C., for a period of between 5 minutes and 72 hours,preferably between 1 hour and 8 hours.

[0165] Step B involves the reduction of a carbamate of formula 2 toobtain an alcohol of formula 3. The reduction is conducted in thepresence of: 1) a reducing agent, preferably an aluminum hydride orborohydride, such as lithium tri-t-butoxyaluminum hydride; and 2) apolar organic solvent, preferably an ether such as diethyl ether ortetrahydrofuran, at a temperature of between −100° C. and 0° C.,preferably at −78° C., for a period of between 1 hour and 72 hours,preferably for 16 hours.

[0166] Step C involves the silylation of an alcohol of formula 3 toobtain an ether of formula 4. The silylation is conducted in thepresence of: 1) a silylating reagent, preferably at-butyldimethylsilylating reagent such as t-butyldimethylsilyltriflate;2) a weak base, preferably a nitrogen-containing base, more preferably apyridine base such as 2,6-lutidine; and 3) an inert organic solvent,preferably a halogenated hydrocarbon such as methylene chloride, at atemperature of between −100° C. and 5° C., preferably at −20° C., for aperiod of between 10 minutes and 48 hours, preferably for 2 hours.

[0167] As to the individual steps in Scheme 18, Step A involves theoxidation an aldehyde of formula 1 to obtain a carboxylic acid offormula 2. The oxidation is conducted in the presence of: 1) anoxidizing agent such as sodium chlorite; 2) a phosphate salt, preferablysodium dihydrogenphosphate; 3) a protic organic solvent, preferably analcohol such as t-butanol; and 4) an alkene, preferably 2-methylpropene,at a temperature of between 0° C. and 40° C., preferably at 25° C., fora period of between 10 minutes and 8 hours, preferably for 1 hour.

[0168] Step B involves the reductive amination of an aldehyde of formula1 to obtain an amine of formula 3. The reductive amination is conductedin the presence of: 1) an amine of formula R₅NH₂, where R₅ is as definedabove; 2) a reducing agent, preferably a hydride, more preferably aborohydride salt such as sodium borohydride; and 3) a polar organicsolvent, preferably a protic organic solvent such as ethanol, at atemperature of between 0° C. and 40° C., preferably from 5° C. to 25°C., for a period of between 10 minutes and 48 hours, preferably for 16hours.

[0169] Step C involves the azidation of an iodide of formula 4 to obtainan azide of formula 5. The azidation is conducted in the presence of: 1)an azide salt such as sodium azide; and 2) a polar organic solvent suchas DMF, at a temperature of between 25° C. and 150° C., preferably at90° C., for a period of between 10 minutes and 48 hours, preferably for16 hours.

[0170] Step D involves the reduction of an azide of formula 5 to obtainan amine of formula 6. The azidation is conducted in the presence of: 1)a reducing agent, preferably a phosphine such as triphenylphoshine inthe presence of water; and 2) a polar organic solvent such astetrahydrofuran, at a temperature of between 0° C. and 100° C.,preferably from 25° C. to 60° C., for a period of between 10 minutes and48 hours, preferably for 16 hours.

[0171] As to the individual steps in Scheme 19, Step A involves thereduction of an aldehyde of formula 1 to obtain an alcohol of formula 2.The reduction is conducted in the presence of: 1) a hydride reducingagent reagent, preferably an aluminum hydride such as lithium aluminumhydride or diisobutylaluminum hydride, or a borohydride such as sodiumborohydride; and 2), a polar organic solvent, preferably an ether suchas tetrahydrofuran, at a temperature of between −100° C. and 40° C.,preferably from −20° C. to 25° C., for a period of between 10 minutesand 48 hours, preferably for 2 hours.

[0172] Step B involves the silylation of an alcohol of formula 2 toobtain a silyl ether of formula 3. The silylation is conducted in thepresence of: 1) a silylating reagent, preferably at-butyldimethylsilylating reagent such as t-butyldimethylsilyltriflate;2) a weak base, preferably a nitrogen-containing base, more preferably apyridine base such as 2,6-lutidine; and 3) an inert organic solvent,preferably a halogenated hydrocarbon such as methylene chloride, at atemperature of between −100° C. and 5° C., preferably at −20° C., for aperiod of between 10 minutes and 48 hours, preferably for 2 hours.

[0173] Step C involves the reductive hydrolysis of a silyl ether offormula 3 to obtain an alcohol of formula 4. The reductive hydrolysis isconducted in the presence of: 1) a Lewis acidic hydride, preferably analuminum hydride such as diisobutylaluminumhydride; and 2) a polarorganic solvent, preferably a halogenated hydrocarbon such as methylenechloride, at a temperature of between −100° C. and 5° C., preferably at−78° C., for a period of between 10 minutes and 48 hours, preferably for1 hour.

[0174] Step D involves the oxidation of an alcohol of formula 4 toobtain an aldehyde of formula 5. The oxidation is conducted in thepresence of: 1) an oxidizing reagent, preferably a mild oxidizingreagent such as the combinations of oxalyl chloride, DMSO andtriethylamine; sulfur trioxide-pyridine complex, DMSO and triethylamine;and 2,2,6,6-tetramethyl-1-piperidinyloxy free radical anddiacetoxyiodobenzene; and 2) an inert organic solvent, preferably apolar organic solvent such as methylene chloride, at a temperature ofbetween −78° C. and 40° C., preferably from −20° C. to 25° C., for aperiod of between 10 minutes and 48 hours, preferably for 3 hours.

[0175] Step E involves the olefination of an aldehyde of formula 5 toobtain a diene of formula 6. The olefination is conducted in thepresence of: 1) a halogenated silyl propene such as1-bromo-1-trimethylsilyl-2-propene; 2) a chromium(II) reagent such aschromium(II)chloride; and 3) a polar organic solvent, preferably anether such as tetrahydrofuran, at a temperature of between −100° C. and40° C., preferably at 20° C., for a period of between 10 minutes and 48hours, preferably for 3 hours.

[0176] Step F involves the hydrolysis of a diene of formula 6 to obtainan alcohol of formula 7. The hydrolysis is conducted in the presenceof: 1) a protic acid, preferably a hydrogen halide such as hydrochloricacid; and 2) a polar organic solvent, preferably an ether such astetrahydrofuran, at a temperature of between −10° C. and 40° C.,preferably at 20° C., for a period of between 10 minutes and 48 hours,preferably for 1 hour.

[0177] Step G involves the oxidation of an alcohol of formula 7 toobtain an aldehyde of formula 8. The oxidation is conducted in thepresence of: 1) an oxidizing reagent, preferably a mild oxidizingreagent such as the combinations of oxalyl chloride, DMSO andtriethylamine; sulfur trioxide-pyridine complex, DMSO and triethylamine;and 2,2,6,6-tetramethyl-1-piperidinyloxy free radical anddiacetoxyiodobenzene; and 2) an inert organic solvent, preferably apolar organic solvent such as methylene chloride, at a temperature ofbetween −78° C. and 40° C., preferably from −20° C. to 25° C., for aperiod of between 10 minutes and 48 hours, preferably for 3 hours.

[0178] Step H involves the propionate addition reaction of an aldehydeof formula 8 to obtain an imide of formula 10. The propionate additionreaction is conducted in the presence of: 1) a propanimide of formula 9;2) a Lewis acid, preferably a boron-containing Lewis acid such asdibutylborontriflate; 3) a weak base, preferably an amine base such astriethylamine; and 4) an inert organic solvent, preferably a polarorganic solvent such as methylene chloride, at a temperature of between−100° C. and 20° C., preferably from −78° C. to 0° C., for a period ofbetween 10 minutes and 48 hours, preferably for 2 hours.

[0179] Step I involves the silylation of an alcohol of formula 10 toobtain a silyl ether of formula 11. The silylation is conducted in thepresence of: 1) a silylating reagent, preferably at-butyldimethylsilylating reagent such as t-butyldimethylsilyltriflate;2) a weak base, preferably a nitrogen-containing base, more preferably apyridine base such as 2,6-lutidine; and 3) an inert organic solvent,preferably a halogenated hydrocarbon such as methylene chloride, at atemperature of between −100° C. and 5° C., preferably at −20° C., for aperiod of between 10 minutes and 48 hours, preferably for 2 hours.

[0180] As to the individual steps in Scheme 20, Step A involves thehydrolysis of an imide of formula 1 to obtain a carboxylic acid offormula 2. The hydrolysis is conducted in the presence of: 1) a strongbase, preferably a hydroxide salt such as lithium hydroxide; 2) anoxidant, preferably a peroxide such as hydrogen peroxide; and 3) a polarorganic solvent, preferably an ether such as tetrahydrofuran, at atemperature of between −20° C. and 40° C., preferably from −10° C. to25° C., for a period of between 10 minutes and 48 hours, preferably for18 hours.

[0181] Step B involves the reduction of an imide of formula 1 to obtainan alcohol of formula 3. The reduction is conducted in the presenceof: 1) a hydride reducing agent such as lithium borohydride; 2) a proticorganic solvent, preferably a lower alkanol such as ethanol; and 3) apolar organic solvent, preferably an ether such as tetrahydrofuran, at atemperature of between −20° C. and 40° C., preferably at 25° C., for aperiod of between 10 minutes and 48 hours, preferably for 18 hours.

[0182] Step C involves the acylation of an imide of formula 1 to obtainan amide of formula 4. The acylation is conducted in the presence of: 1)N,O-dimethylhydroxylamine hydrochloride; 2) an organoaluminum reagentsuch as trimethylaluminum; and 3) a polar organic solvent, preferably anether such as tetrahydrofuran, at a temperature of between −78° C. and40° C., preferably at −20° C., for a period of between 10 minutes and 8hours, preferably for 2 hours.

[0183] Step D involves the oxidation of an alcohol of formula 3 toobtain an aldehyde of formula 5. The oxidation is conducted in thepresence of: 1) an oxidizing reagent, preferably a mild oxidizingreagent such as the combinations of oxalyl chloride, DMSO andtriethylamine; sulfur trioxide-pyridine complex, DMSO and triethylamine;and 2,2,6,6-tetramethyl-1-piperidinyloxy free radical anddiacetoxyiodobenzene; and 2) an inert organic solvent, preferably apolar organic solvent such as methylene chloride, at a temperature ofbetween −78° C. and 40° C., preferably from −20° C. to 25° C., for aperiod of between 10 minutes and 48 hours, preferably for 3 hours.

[0184] Step E involves the reduction of an amide of formula 4 to obtainan aldehyde of formula 5. The reduction is conducted in the presenceof: 1) a metal hydride, preferably an aluminum hydride such as lithiumaluminum hydride or diisobutylaluminum hydride; and 2) a polar organicsolvent, preferably an ether such as tetrahydrofuran, at a temperatureof between −100° C. and 10° C., preferably from −78° C. to 0° C., for aperiod of between 10 minutes and 8 hours, preferably for 2 hours.

[0185] Step F involves the reductive amination of an aldehyde of formula5 to obtain an amine of formula 6. The reductive amination is conductedin the presence of: 1) an amine of formula R₅NH₂, where R₅ is as definedabove; 2) a reducing agent, preferably a hydride, more preferably aborohydride salt such as sodium borohydride; and 3) a polar organicsolvent, preferably a protic organic solvent such as ethanol, at atemperature of between 0° C. and 40° C., preferably from 5° C. to 25°C., for a period of between 10 minutes and 48 hours, preferably for 16hours.

[0186] Step G involves the mesylation of an alcohol of formula 3 toobtain a mesylate of formula 7. The mesylation is conducted in thepresence of: 1) methanesulfonyl chloride; 2) a base, preferably an aminebase such as triethylamine; and 3) a polar organic solvent, preferably ahalogenated hydrocarbon such as such as methylene chloride, at atemperature of between −20° C. and 40° C., preferably from 0° C. to 5°C., for a period of between 10 minutes and 8 hours, preferably for 2hours.

[0187] Step H involves the azidation of a mesylate of formula 7 toobtain an azide of formula 8. The azidation is conducted in the presenceof: 1) an azide salt such as sodium azide; and 2) a polar organicsolvent such as DMF, at a temperature of between 25° C. and 150° C.,preferably at 90° C., for a period of between 10 minutes and 48 hours,preferably for 16 hours.

[0188] Step I involves the reduction of an azide of formula 8 to obtainan amine of formula 9. The azidation is conducted in the presence of: 1)a reducing agent, preferably a phosphine such as triphenylphoshine inthe presence of water; and 2) a polar organic solvent such astetrahydrofuran, at a temperature of between 0° C. and 100° C.,preferably from 25° C. to 60° C., for a period of between 10 minutes and48 hours, preferably for 16 hours.

[0189] Although the product of each reaction described above may, ifdesired, be purified by conventional techniques such as chromatographyor recrystallization (if a solid), the crude product of one reaction isadvantageously employed in the following reaction without purification.

[0190] As is evident to those skilled in the art, compounds of formula Icontain asymmetric carbon atoms. It should be understood, therefore,that the individual stereoisomers are contemplated as being includedwithin the scope of this invention.

[0191] As indicated above, all of the compounds of formula I areanti-tumor agents and are, therefore, useful in inhibiting the growth ofvarious lymphomas, sarcomas, carcinomas, myelomas, and leukemia celllines. The anti-tumor activity of the compounds of formula I may bedemonstrated employing the Anchorage Dependent Growth Monolayer Assay(ADGMA) which measures the growth inhibitory effects of test compoundson proliferation of adherent cell monolayers. This assay was adaptedfrom the 60 cell line assay used by the National Cancer Institute (NCI)with the following modifications: 1) four cell lines representative forthe important tumor types, viz., MIP 101 colon carcinoma, HCT 116 coloncarcinoma, 1A9 ovarian carcinoma and 1A9PTX22 ovarian carcinoma, wereutilized; and 2) a tetrazolium derivative, viz., MTT, was utilized todetermine cell density.

[0192] The ADGMA compares the number of viable cells following a 3-dayexposure to a test compound relative to the number of cells present atthe time the test compound was added. Cell viability is measured using atetrazolium derivative, viz.,3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide (MTT) thatis metabolically reduced in the presence of an electron coupling agent(PMS; phenazine methosulfate) by viable cells to a water-solubleformazan derivative. The absorbance at 540 nm (A540) of the formazanderivative is proportional to the number of viable cells. The IC₅₀ for atest compound is the concentration of compound required to reduce thefinal cell number to 50% of the final control cell number. If cellproliferation is inhibited, the assay further defines compounds ascytostatic (cell number after 3-day compound incubation>cell number attime of compound addition) or cytotoxic (cell number after 3-daycompound incubation<cell number at time of compound addition).

[0193] The HCT 116 colon carcinoma cell line was obtained from theAmerican Type Culture Collection (ATCC, Rockville, Md.). The MIP 101colon carcinoma cell line was obtained from Dr. Robert Kramer (BristolMeyers Squibb) and was previously described (Niles R M, Wilhelm S A,Steele G D JR, Burke B, Christensen T, Dexter D, O'Brien M J, Thomas P,Zamcheck N. Isolation and characterization of an undifferentiated humancolon carcinoma cell line (MIP-101). Cancer Invest. 1987;5(6):545-52.).The 1A9 and the 1A9PTX22 ovarian tumor cell lines were obtained from Dr.Tito Fojo, Medicine Branch, Division of Clinical Sciences, NationalCancer Institute, National Institutes of Health, Bethesda, Md. 20892.The 1A9 is a clone of the ovarian carcinoma cell line, A2780(Giannakakou P, Sackett, D L, Kang Y-K, Zhan Z, Buters J T M, Fojo T,Poruchynsky M S. Paclitaxel-resistant human ovarian cancer cells havemutant 8-tubulins that impaired paclitaxel-driven polymerization. J.Biol. Chem. 1997, 272(4):17118-17125). The 1A9PTX22 subline was isolatedas an individual clone from the 1A9 cell line in a single step selectionby exposure to 5 ng/mL paclitaxel in the presence of 5 μg/mL ofverapamil. All cell lines were used between passages 4-20 followingthawing. MIP-101 colon carcinoma, HCT 116 colon carcinoma, 1A9 ovariancarcinoma and 1A9PTX22 ovarian carcinoma cell lines are maintained andplated in RPMI 1640 medium containing 10% fetal bovine serum.

[0194] Cells are trypsinized and counted using a hemacytometer todetermine cell concentrations. Cells were then plated in theirrespective maintenance media (200 μL/well) in 96-well plates at thefollowing concentrations: MIP-101, 2000 cells/well; HCT 116, 2000cells/well; 1A9, 10000 cells/well; and 1A9PTX22, 10000 cells/well. Thenumber of cells/well was determined in preliminary experiments, andresulted in 75-90% of confluency by day 4 after plating. Initial celldensities, assayed one day after plating, are roughly 0.10-0.20 A540absorbance units greater than the media blank. Ninety-six well plateswere seeded on day 0 and the test compounds are added on day 1. A “time0” plate was created that received media only in row A and one cellline/row in rows B-E. The “time 0” plate was processed 24 hours afterplating (at the time when drugs were added to experimental plates), asfollows: 5 micoliters of the MTT stock solution (0.5 mg/mL in PBS) wasadded to each well and then incubated for three hours at 37° C., 5% CO₂,in a humidified environment. Media was then carefully and completelyremoved. Plates were allowed to dry in the dark. DMSO(dimethylsulfoxide) was added to each well (100 μL/well) and plates wereplaced on an orbital shaker for 2 hours. Plates were read in the 96-wellplate reader at 540 nm in a Molecular Devices plate reader utilizingSoftmax Version 2.35 in absorbance mode-endpoint L-1, using DMSO as ablank. One day following plating, test compounds were added (in a final1:10 dilution) to the test plates and subsequently serial diluted 10times. Control plate received 1:10 dilution of the solvent (10% DMSO/90%RPMI 1640) only. Three days after addition of test compounds, all theexperimental plates and the control plate were processed as describedabove for the “time 0” plate. IC₅₀ values are determined from graphs ofpercent net growth as a function of compound concentration. Percent netgrowth is calculated as (Cell+Drug A540−Initial 540/Cell+Drug Vehicle540−Initial 540).

[0195] The following IC₅₀ values (average of two or more separateexperiments) in μM were obtained: Compound MIP101 HCT116 1A9 1A9PTX22Ex. 1 3.8 0.2 0.03 0.18 Ex. 2 20 13 4 6 paclitaxel 0.2 0.0003 0.0470.001 (a known antineoplastic compound)

[0196] The precise dosage of the compounds of formula I to be employedfor inhibiting tumors depends upon several factors including the host,the nature and the severity of the condition being treated, the mode ofadministration and the particular compound employed. However, ingeneral, satisfactory inhibition of tumors is achieved when a compoundof formula I is administered parenterally, e.g., intraperitoneally,intravenously, intramuscularly, subcutaneously, intratumorally, orrectally, or enterally, e.g., orally, preferably intravenously ororally, more preferably intravenously at a single dosage of 1-300 mg/kgbody weight per cycle (cycle =3-6 weeks) or, for most larger primates, asingle dosage of 50-5000 mg per treatment cycle. A preferred intravenoussingle dosage per 3-6 week treatment cycle is 1-75 mg/kg body weight or,for most larger primates, a daily dosage of 50-1500 mg. A typicalintravenous dosage is 45 mg/kg, once every three weeks.

[0197] Usually, a small dose is administered initially and the dosage isgradually increased until the optimal dosage for the host undertreatment is determined. The upper limit of dosage is that imposed byside effects and can be determined by trial for the host being treated.

[0198] The compounds of formula I may be combined with one or morepharmaceutically acceptable carriers and, optionally, one or more otherconventional pharmaceutical adjuvants and administered enterally, e.g.,orally, in the form of tablets, capsules, caplets, etc. or parenterally,e.g., intraperitoneally or intravenously, in the form of sterileinjectable solutions or suspensions. The enteral and parenteralcompositions may be prepared by conventional means.

[0199] The compounds of formula I may be formulated into enteral andparenteral pharmaceutical compositions containing an amount of theactive substance that is effective for inhibiting tumors, suchcompositions in unit dosage form and such compositions comprising apharmaceutically acceptable carrier.

[0200] The compounds according to the invention can be administeredalone or in combination with one or more other therapeutic agents,possible combination therapy taking the form of fixed combinations orthe administration of a compound of the invention and one or more othertherapeutic agents being staggered or given independently of oneanother, or the combined administration of fixed combinations and one ormore other therapeutic agents. In particular, a compound of formula (I)can be administered, for example, in the case of tumor therapy incombination with chemotherapy, radiotherapy, immunotherapy, surgicalintervention or a combination of these. Long-term therapy is equallypossible as is adjuvant therapy in the context of other treatmentstrategies, as described above. Other possible treatments are therapy tomaintain the patient's status after tumor regression, or evenchemopreventive therapy, for example, in patients at risk.

[0201] Therapeutic agents for possible combination are especially one ormore anti-proliferative, cytostatic or cytotoxic compounds, for example,a chemotherapeutic agent or several agents selected from the group whichincludes, but is not limited to, an inhibitor of polyamine biosynthesis,an inhibitor of a protein kinase, especially of a serine/threonineprotein kinase, such as protein kinase C, or of a tyrosine proteinkinase, such as the EGF receptor tyrosine kinase, e.g., PKI166, the VEGFreceptor tyrosine kinase, e.g., PTK787, or the PDGF receptor tyrosinekinase, e.g., STI571, a cytokine, a negative growth regulator, such asTGF-β or IFN-β, an aromatase inhibitor, e.g., letrozole or anastrozole,an inhibitor of the interaction of an SH2 domain with a phosphorylatedprotein, anti-estrogens, topoisomerase I inhibitors, such as irinotecan,topoisomerase II inhibitors, microtubule active agents, e.g.,paclitaxel, discodermolide or an epothilone, alkylating agents,anti-neoplastic anti-metabolites, such as gemcitabine or capecitabine,platin compounds, such as carboplatin or cisplatin, anti-angiogeniccompounds, gonadorelin agonists, anti-androgens, bisphosphonates, e.g.,AREDIA® or ZOMETA® and trastuzumab. The structure of the active agentsidentified by code nos., generic or trade names may be taken from theactual edition or the standard compendium “The Merck Index” or fromdatabases, e.g., Patents International, e.g, IMS World Publications. Thecorresponding content thereof is hereby incorporated by reference.

[0202] The following examples show representative compounds encompassedby this invention and their synthesis. However, it should be clearlyunderstood that it is for purposes of illustration only.

EXAMPLE 1 Synthesis of(2R,3S,4S,5S,7S,8Z,10S,11S,12S,13Z,16S,17R,18S,19S,20S)-19-[(aminocarbonyl)oxy]-3,5,7,11,17-pentahydroxy-2,3,4,10,12,14,16,18,20-nonamethyl-21-(phenylmethoxy)-8,13-heneicosadienoicacid 6-lactone.

[0203] a) Preparation of(5R,6S,7Z,10S,11R)-11-[(1R,2S,3S)-2-[(4-methoxyphenyl)methoxy]-1,3-dimethyl-4-(phenylmethoxy)butyl]-5-[(1S)-2-[(4-methoxyphenyl)methoxy]-1-methylethyl]-2,2,3,3,6,8,10,13,13,14,14-undecamethyl-4,12-dioxa-3,13-disilapentadec-7-ene.

[0204] NaH (12 mg, 0.49 mmol, 2 eq) is added to a solution of(2S,3S,4R,5R,6S,8Z,10S,11R,12S)-5,11-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3,13-bis[(4-methoxyphenyl)methoxy]-2,4,6,8,10,12-hexamethyl-8-tridecen-1-ol(200 mg, 0.245 mmol, 1 eq) in DMF (3 mL) at −78° C. The reaction isslowly warm to 23° C. and is stirred for 1 h. Benzyl bromide (84 mg,0.49 mmol, 2 eq) and potassium iodide (cat. 1 mg) are added and stirredfor 18 h. The solvent is removed. The crude product is chromatographed(from hexane to 10% EtOAc in hexane) to give 204 mg (80%) of the desiredcompound as a colorless oil.

[0205]¹H NMR (200 MHz, CDCl₃), δ 7.38-7.16 (m, 9H), 6.88-6.79 (d, J=10,4H), 5.01-4.97 (d, J=8, 1H), 4.46-4.34 (m, 6H), 3.76 (s, 6H), 3.52-3.14(m, 8H), 32.52-2.44 (m, 1H), 2.29-2.21 (m, 1H), 2.08-1.86 (m, 4H),1.64-1.53 (m, 5H), 1.03-1.01 (d, J=4, 3H). 0.90-0.86 (m, 25H), 0.70-0.68(d, J=4, 3H), 0.03 to −0.01 (m, 12H); ¹³C NMR (200 MHz, CDCl₃), δ159.04, 138.73, 131.76, 131.37, 131.21, 131.04, 129.06, 129.02, 128.31,127.54, 127.43, 113.74, 113.68, 82.43, 78.35, 74.45, 73.06, 72.70,72.52, 72.32, 55.27, 55.26, 39.00, 38.78, 37.07, 37.00, 35.62, 34.78,26.27, 26.15, 23.15, 18.52, 18.39, 17.08, 15.64, 14.50, 12.84, 11.06,−3.27, −3.86, −3.89. Mass spectrum (ESI), m/z 905, 922 (m+NH₃).

[0206] b) Preparation of(2S,3R,4S,5Z,8S,9R,10R,11S,12S)-3,9-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-2,4,6,8,10,12-hexamethyl-13-(phenylmethoxy)-5-tridecene-1,11-diol.

[0207] Water (3 mL) is added to a solution of(5R,6S,7Z,10S,11R)-11-[(1R,2S,3S)-2-[(4-methoxyphenyl)methoxy]-1,3-dimethyl-4-(phenylmethoxy)butyl]-5-[(1S)-2-[(4-methoxyphenyl)methoxy]-1-methylethyl]-2,2,3,3,6,8,10,13,13,14,14-undecamethyl-4,12-dioxa-3,13-disilapentadec-7-ene(1.0 g, 1.19 mmol) in CH₂Cl₂ (30 mL) at 23° C. and stirred for 5 min.DDQ (1.62 g, 7.14 mmol, 6 eq) is added at once and stirred for 15 min.The product mixture is concentrated. The residue is filtered throughcelite and washed with hexane. The hexane layers are dried andconcentrated. The crude product is chromatographed (from hexane to 10%EtOAc in hexane) to give 630 mg (89%) of the desired compound as acolorless oil.

[0208]¹H NMR (200 MHz, CDCl₃), δ 7.23-7.16 (m, 5H), 4.94-4.91 (d, J=6,1H), 4.43 (s, 2H), 3.57-3.30 (m, 8H), 2.54-2.10 (m, 2H), 1.89-1.56 (m,8H), 1.12-1.10 (d, J=4, 2H), 0.90-0.65 (m, 32H), 0.03 to −0.01 (m, 12H);¹³C NMR (200 MHz, CDCl₃), δ 137.85, 133.43, 130.42, 128.45, 127.76,127.67, 81.58, 78.85, 76.60, 75.68, 73.44, 65.42, 38.63, 38.40, 37.07,36.73, 36.37, 34.65, 26.25, 26.18, 25.37, 18.50, 18.35, 17.39, 15.85,13.70, 12.94, 9.65, −3.49, −3.55, −3.89. Mass spectrum (ESI), m/z 665,682 (m+NH₃).

[0209] c) Preparation of(2R,3R,4S,5Z,8S,9R,10R,11S,12S)-3,9-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-11-hydroxy-2,4,6,8,10,12-hexamethyl-13-(phenylmethoxy)-5-tridecenal.

[0210] TEMPO (21 mg, 0.136 mmol, 0.2 eq) is added to a solution of(2S,3R,4S,5Z,8S,9R,10R,11S,12S)-3,9-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-2,4,6,8,10,12-hexamethyl-13-(phenylmethoxy)-5-tridecene-1,11-diol(450 mg, 0.68 mmol) in CH₂Cl₂ (4 mL) and stirred for 5 min at 23° C.BAIB (263 mg, 0.816 mmol, 1.2 eq) is added to the reaction mixture andstirred for 2 h. CH₂Cl₂ (7 mL) and saturated Na₂S₂O₃ are added to themixture. The organic layer is separated, washed with brine and dried.The solvent is removed to give 438 mg of crude product. The crudeproduct is used for the next step.

[0211] Mass spectrum (ESI), m/z 663, 680(m+NH₃).

[0212] d) Preparation of(2Z,4S,5S,6S,7Z,10S,11R,12R,13S,14S)-5,11-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-13-hydroxy-4,6,8,10,12,14-hexamethyl-15-(phenylmethoxy)-2,7-pentadecadienoicacid methyl ester.

[0213] 18-Crown-6 (349 mg, 1.32 mmol, 2 eq) is added to a solution ofbis(2,2,2-trifluoroethyl) (methoxycarbonylmethyl)phosphonate (355 mg,1.78 mmol, 2.7 eq) in toluene (7 mL) at 23° C. and stirred for 5 min.The mixture is cooled to −20° C. KHMDS (1.78 mmol, 2.7 eq, 0.5 M intoluene) is added dropwise and stirred for 30 min. The mixture is warmedto 0° C. and stirred for 30 min. Then the mixture is cooled to −20° C.,a solution of crude(2R,3R,4S,5Z,8S,9R,10R,11S,12S)-3,9-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-11-hydroxy-2,4,6,8,10,12-hexamethyl-13-(phenylmethoxy)-5-tridecenalin toluene (3 mL) is added to the mixture and stirred for 5 min. Themixture is warmed to 0° C. and stirred for 4 h. Saturated NH₄Cl (15 mL)is added, and the resultant mixture is washed with brine, dried andconcentrated. The crude product is chromatographed (10% EtOAc in hexane)to give 266 mg (two-step: 52%) of the desired compound as a colorlessoil.

[0214]¹H NMR (200 MHz, CDCl₃), δ 7.26-7.19 (m, 5H), 6.33-6.26 (t, J=6,1H), 5.64-5.60 (d, J=8, 1H), 4.86-4.83 (d, J=7, 1H), 4.44 (s, 2H),3.59-3.24 (m, 11H), 2.27-2.06 (m, 2H), 1.88-1.48 (m, 8H), 0.94-0.60 (m,32H), 0.02 to −0.01 (m, 12H); ¹³C NMR (200 MHz, CDCl₃), δ 166.48,152.52, 137.85, 132.96, 130.15, 128.46, 127.76, 127.66, 118.47, 80.64,78.81, 76.61, 75.90, 73.45, 50.86, 38.45, 37.90, 37.44, 36.33, 36.27,34.58, 26.23, 23.14, 18.49, 18.45, 18.27, 18.22, 13.72, 13.12, 9.50,−3.36, −3.57, −3.62. Mass spectrum (ESI), m/z 719, 736 (m+NH₃).

[0215] e) Preparation of(2Z,4S,5S,6S,7Z,10S,11R,12R,13S,14S)-13-[(aminocarbonyl)oxy]-5,11-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4,6,8,10,12,14-hexamethyl-15-(phenylmethoxy)-2,7-pentadecadienoicacid methyl ester.

[0216] Trichloroacetyl isocyanate (106 mg, 0.56 mmol, 1.5 eq) is addedto a solution of(2Z,4S,5S,6S,7Z,10S,11R,12R,13S,14S)-5,11-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-13-hydroxy-4,6,8,10,12,14-hexamethyl-15-(phenylmethoxy)-2,7-pentadecadienoicacid methyl ester (266 mg, 0.37 mmol) in CH₂Cl₂ (5 mL) at 23° C. Themixture is stirred for 30 min. The solvent is removed. The residue ischromatographed (10% EtOAc in hexane) to give 208 mg (74%) of thedesired compound as a white foam.

[0217]¹H NMR (200 MHz, CDCl₃), δ 7.24-7.19 (m, 5H), 6.33-6.26 (t, J=6,1H), 5.64-5.61 (d, J=8, 1H), 4.84-4.81 (d, J=7, 1H), 4.66-4.63 (m, 1H),4.48-4.40(m, 4H), 3.59-3.16 (m, 8H), 2.30-1.82 (m, 4H), 1.56-1.51 (m,6H), 0.94-0.57 (m, 32H), 0.04 to −0.01 (m, 12H); ¹³C NMR (200 MHz,CDCl₃),δ 166.51, 156.80, 152.49, 138.52, 132.86, 130.06, 128.30, 127.66,127.48, 118.46, 80.58, 77.68, 76.91, 76.59, 73.24, 72.29, 50.89, 37.90,37.45, 37.39, 36.28, 36.10, 34.83, 31.59, 26.20, 22.89, 22.66, 18.47,18.29, 18.21, 14.75, 14.14, 12.97, 10.39, −3.37, −3.60, −3.64. Massspectrum (ESI), m/z 762, 779 (m+NH₃).

[0218] f) Preparation of(2Z,4S,5S,6S,7Z,10S,11R,12R,13S,14S)-5,11-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4,6,8,10,12,14-hexamethyl-15-(phenylmethoxy)-2,7-pentadecadiene-1,13-diol-13-carbamate.

[0219] A solution of(2Z,4S,5S,6S,7Z,10S,11R,12R,13S,14S)-13-[(aminocarbonyl)oxy]-5,11-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4,6,8,10,12,14-hexamethyl-15-(phenylmethoxy)-2,7-pentadecadienoicacid methyl ester (208 mg, 0.27 mmol) in CH₂Cl₂ (4 mL) is treated withDIBAL-H (1.08 mmol, 4 eq, 1 N in hexane) at −78° C. The mixture isstirred for 2 h. Saturated Rochelle's salt solution is added to themixture. The mixture is extracted with ether, washed with brine anddried over MgSO₄. The solvent is removed. The residue is chromatographed(10% to 20% EtOAc in hexane) to give 152 mg (77%) of the desiredcompound as a slightly yellow oil.

[0220]¹H NMR (200 MHz, CDCl₃), δ 7.28-7.20 (m, 5H), 5.53-5.45 (m, 1H),4.94-4.90 (d, J=8, 1H), 4.71-4.42 (m, 4H), 4.08-4.03 (m, 2H), 3.48-3.18(m, 4H), 2.61-1.57 (m, 12H), 0.94-0.63 (m, 32H), 0.02-0.0 (m, 12H); ¹³CNMR (200 MHz, CDCl₃), δ 157.40, 138.90, 135.02, 133.05, 128.93, 128.71,128.10, 127.70, 81.22, 77.85, 73.69, 73.01, 59.37, 38.31, 37.56, 37.45,37.38, 36.91, 36.52, 34.81, 32.00, 26.64, 23.16, 19.76, 18.91, 18.27,15.09, 14.55, 12.79, 10.83, −2.64, −3.09, −3.21. Mass spectrum (ESI),m/z 734, 751 (m+NH₃).

[0221] g) Preparation of unsaturated(2Z,4S,5S,6S,7Z,10S,11R,12R,13S,14S)-13-[(aminocarbonyl)oxy]-5,11-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4,6,8,10,12,14-hexamethyl-15-(phenylmethoxy)-2,7-pentadecadienal.

[0222] A solution of(2Z,4S,5S,6S,7Z,10S,11R,12R,12S,14S)-5,11-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4,6,8,10,12,14-hexamethyl-15-(phenylmethoxy)-2,7-pentadecadiene-1,13-diol-13-carbamate(198 mg, 0.37 mmol) in CH₂Cl₂ (2 mL) is added to a solution ofDess-Martin reagent (138 mg, 0.324 mmol, 1.2 eq) in CH₂Cl₂ (2 mL) at 23°C. The mixture is stirred for 1 h. Saturated Na₂S₂O₃ is added to themixture. The organic layer is separated, washed with brine and driedover MgSO₄. The solvent is removed. The residue is chromatographed (10%EtOAc in hexane) to give 190 mg (95%) of the desired compound as acolorless oil. This aldehyde is used immediately. Mass spectrum (ESI),m/z 732, 751 (m+NH₃).

[0223] h) Preparation of(2R,3S,4R,7S,8Z,10S,11S,12S,13Z,16S,17R,18R,19S,20S)-19-[(aminocarbonyl)oxy]-3,11,17-tris[[(1,1-dimethylethyl)dimethylsilyl]oxy]-7-hydroxy-N-methoxy-N,2,4,10,12,14,16,18,20-nonamethyl-5-oxo-21-(phenylmethoxy)-8,13-heneicosadienamide.

[0224] A solution of (+)-DIP-Cl (963 mg, 3.0 mmol, 11 eq) in ether (2mL) is treated with fresh distilled Et₃N (320 mg, 3.16 mmol, 11.7 eq) at−5° C. and stirred for 30 min. A solution of(2R,3S,4R)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-N-methoxy-N-methyl-2,4-trimethyl-5-oxo-hexanamide(895 mg, 2.7 mmol, 10 eq) in ether (2 mL) is added through a cannula.The mixture is stirred for 2 h at −5° C. Then the mixture is cooled to−78° C. A solution of(2Z,4S,5S,6S,7Z,10S,11R,12R,13S,14S)-13-[(aminocarbonyl)oxy]-5,11-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4,6,8,10,12,14-hexamethyl-15-(phenylmethoxy)-2,7-pentadecadienal(190 mg, 0.26 mmol) in ether (2 mL) is added dropwise to the mixture andstirred for 3 h. The mixture is warmed to −20° C., MeOH (4 mL),phosphate buffer (pH=7.4, 4 mL) and H₂O₂ (30%, 4 mL) are added to quenchthe reaction and the resultant mixture is stirred for 2 h at −20° C. Theorganic layer is extracted with EtOAc, washed with brine and dried overMgSO₄. The solvent is removed. The crude product is chromatographed (20%EtOAc in hexane) to give 173 mg (60%) of the desired compound as acolorless oil.

[0225]¹H NMR (200 MHz, CDCl₃), δ 7.25-7.18 (m, 5H), 5.46-5.38 (m, 1H),5.29-5.22(t, J=7, 1H), 5.00-4.97 (d, J=6, 1H), 4.74-4.44 (m, 4H),4.35-4.27 (m, 2H), 4.25-4.22 (m, 1H), 3.66 (s, 3H), 3.66-2.73 (m, 7H),2.73-2.38 (m, 6H), 2.21-1.56(m, 9H), 1.12-0.63 (m, 48H), 0.04 to −0.04(m, 18H); ¹³C NMR (200 MHz, CDCl₃), δ 213.43, 175.88, 156.89, 138.55,136.00, 132.09, 131.26, 129.67, 128.29, 127.66, 127.46, 80.66, 77.04,76.61, 74.02, 73.26, 72.63, 64.92, 61.30, 60.40, 53.13, 49.08, 38.19,37.62, 37.11, 36.19, 36.02, 34.59, 32.00, 26.26, 26.24, 26.01, 23.00,19.76, 18.63, 18.49, 18.47, 18.18, 16.49, 14.95, 14.68, 12.34, 11.04,10.45, −3.22, −3.29, −3.55, −3.87, −4.07, −4.42. Mass spectrum (ESI),m/z 1063.

[0226] i) Preparation of(2R,3S,4S,5S,7S,8Z,10S,11S,12S,13Z,16S,17R,18R,19S,20S)-19-[(aminocarbonyl)oxy]-3,11,17-tris[[(1,1-dimethylethyl)dimethylsilyl]oxy]-5,7-dihydroxy-N-methoxy-N,2,4,10,12,14,16,18,20-nonamethyl-21-(phenylmethoxy)-8,13-heneicosadienamide.

[0227] A solution of tetramethylammonium triacetoxyborohydride (263 mg,1 mmol, 10 eq) in MeCN/HOAc (1:1, 1.1 mL) is stirred for 1 h at 23° C.and cooled to −30° C. A solution of(2R,3S,4R,7S,8Z,10S,11S,12S,13Z,16S,17R,18R,19S,20S)-19-[(aminocarbonyl)oxy]-3,11,17-tris[[(1,1-dimethylethyl)dimethylsilyl]oxy]-7-hydroxy-N-methoxy-N,2,4,10,12,14,16,18,20-nonamethyl-5-oxo-21-(phenylmethoxy)-8,13-heneicosadienamide(103 mg, 0.1 mmol)in MeCN (1 mL) is added dropwise. The mixture isstirred for 14 h at −30° C. Saturated Rochelle's salt solution is addedand the resultant stirred for 30 min. Then the mixture is warmed to 23°C. CH₂Cl₂ (5 mL) is added to the mixture. The organic layer isseparated, washed with brine and dried over MgSO₄. The solvent isremoved. The crude product is chromatographed (20% EtOAc in hexane) togive 80 mg (80%) of the desired compound as a colorless oil.

[0228]¹H NMR (200 MHz, CDCl₃), δ 7.26-7.21 (m, 5H), 5.42-5.29 (m, 2H),4.96-4.92 (d, J=8, 1H), 4.67-4.41 (m, 6H), 4.12-4.07 (m, 1H), 3.67 (s,3H), 3.46-3.05 (m, 8H), 2.64-1.87 (m, 6H), 2.21-1.53(m, 10H), 1.26-0.62(m, 48H), 0.06 to −0.06 (m, 18H); ¹³C NMR (200 MHz, CDCl₃), δ 175.75,156.80, 138.51, 136.13, 132.13, 131.06, 129.91, 128.67, 127.36, 127.49,80.63, 77.09, 76.59, 74.45, 73.89, 73.25, 72.71, 64.88, 61.38, 60.37,53.14, 49.10, 38.21, 37.59, 37.13, 36.20, 36.05, 34.61, 32.02, 26.29,26.25, 26.04, 23.03, 19.76, 18.71, 18.51, 18.46, 18.15, 16.48, 14.96,14.62, 12.37, 11.00, 10.43, −3.30, −3.33, −3.46, −3.82. Mass spectrum(ESI), m/z 1065.

[0229] j) Preparation of(2R,3S,4S,5S,7S,8Z,10S,11S,12S,13Z,16S,17R,18S,19S,20S)-19-[(aminocarbonyl)oxy]-3,5,7,11,17-pentahydroxy-2,3,4,10,12,14,16,18,20-nonamethyl-21-(phenylmethoxy)-8,13-heneicosadienoicacid 6-lactone.

[0230] 4 N HCl (0.5 mL) is added dropwise to a stirred solution of(2R,3S,4S,5S,7S,8Z,10S,11S,12S,13Z,16S,17R,18R,19S,20S)-19-[(aminocarbonyl)oxy]-3,11,17-tris[[(1,1-dimethylethyl)dimethylsilyl]oxy]-5,7-dihydroxy-N-methoxy-N,2,4,10,12,14,16,18,20-nonamethyl-21-(phenylmethoxy)-8,13-heneicosadienamide(80 mg, 0.075 mmol) in isopropanol (0.5 mL) at 0° C. After being warmedto 23° C., the mixture is stirred for 40 h. The mixture is then cooledto 0° C. and saturated NaHCO₃ is added to neutralize the mixture topH=7. The solvent is removed. The crude product is purified by HPLC togive 5 mg of the desired compound (15%) as a white powder.

[0231]¹H NMR (500 MHz, CDCl₃), δ 7.34-7.24 (m, 5H), 5.56-5.48 (m, 1H),5.45-5.38(t, J=6, 1H), 5.23-5.14 (d, J=7, 1H), 4.84-4.70 (m, 3H),4.69-4.62 (m, 1H), 4.52-4.44(m, 2H), 3.72 (b, 1H), 3.51-3.5.47 (m, 1H),3.37-3.28 (m, 2H), 3.25-3.20 (m, 1H), 2.90-2.79 (m, 1H), 2.75-2.60 (m,2H), 2.60-2.20 (m, 2H), 2.17-2.12 (m, 1H), 2.08-1.90 (m, 5H), 1.89-1.82(m, 1H), 1.75-1.54 (m, 7H), 1.37-1.32 (m, 3H), 1.12-0.91 (m, 15H),0.88-0.82 (m, 3H); ¹³C NMR (200 MHz, CDCl₃), δ 173.98, 157.20, 138.45,134.45, 133.60, 132.82, 129.516, 128.32, 127.68, 127.51, 79.01, 77.46,76.75, 75.75, 73.25, 73.17, 72.54, 64.45, 43.12, 40.93, 37.17, 36.48,36.40, 36.16, 35.63, 35.48, 32.60, 23.35, 18.36, 15.92, 15.59, 14.45,13.26, 12.59, 8.93. HRMS calcd for C₃₇H₆₀NO₉ (M+H)+662.4268, found662.4284.

EXAMPLE 2 Synthesis of(2R,3S,4R,5S,7S,8Z)-13-[[(2R,3S,4S,5S,6S,7Z)-5-[(aminocarbonyl)oxy]-3-hydroxy-2,4,6-trimethyl-1-oxo-7,9-decadienyl]methylamino]-3,5,7,11-tetrahydroxy-2,4,10,12-tetramethyl-8-tridecenoicAcid 6-lactone.

[0232] a) Preparation of1,2,4-trideoxy-3-O-[(1,1-dimethylethyl)dimethylsilyl]-5-O-[(4-methoxyphenyl)methyl]-2,4-dimethyl-1-(methylamino)-L-arabinitol.

[0233] A solution of2,4-dideoxy-3-O-[(1,1-dimethylethyl)dimethylsilyl]-5-O-[(4-methoxyphenyl)methyl]-2,4-dimethyl-L-arabinose (2.8 g, 7.37 mmol) in THF (10 mL) isadded slowly to a stirred solution of methylamine (14.7 mL, 29.5 mmol)in THF at room temperature. After being stirred at room temperature for20 min, sodium triacetoxyborohydride (2.3 g, 11.05 mmol), followed byacetic acid (10 drops) are added at room temperature. After beingstirred at room temperature overnight, the reaction mixture is dilutedwith EtOAc (100 mL), and washed with saturated NaHCO₃ (2×30 mL), H₂O (50mL), brine (50 mL) and dried over Na₂SO₄. After removal of the solventin vacuo, the residue is chromatographed on silica gel with MeOH/CH₂Cl₂(1/99) to give the desired compound (1.54 g, 52.9%) as a pale viscousoil.

[0234]¹H NMR (CDCl₃, 500 MHz), δ 7.25 (d, J=8.24 Hz, 2H), 6.87 (d,J=8.70 Hz, 2H), 4.42 (dd, J=18.76, 11.60 Hz, 2H), 3.80 (s, 3H), 3.62(dd, J=6.11, 2.45 Hz, 1H), 3.51 (dd, J=9.16, 5.04 Hz, 1H), 3.24 (dd,J=9.00, 7.47 Hz, 1H), 2.53 (dd, J=11.59, 6.86 Hz, 1H), 2.40 (m, 1H),2.63 (s, 3H), 1.96 (m, 1H), 1.80 (m, 1H), 0.98 (d, J=7.02 Hz, 1H), 0.95(d, J=6.86 Hz, 3H), 0.88 (s, 9H), 0.87 (d, J=6.80, 3H), 0.04 (s, 3H),0.03 (s, 3H); ¹³C NMR (CDCl₃, 125 MHz), δ 159.1, 130.8, 129.2, 129.1,113.7, 75.4, 72.8, 72.7, 56.6, 55.3, 38.1, 36.4, 36.1, 26.1, 26.0, 18.4,15.0, 13.0, −4.0, −4.1.

[0235] b) Preparation of2,4-dideoxy-3,5-O-[(4-methoxyphenyl)methylene]-2,4-dimethyl-L-arabinitol.

[0236] A suspension of LiAlH₄ (5.33 g, 37.95 mmol) in THF (250 mL) iscooled to −74° C.2,4-dideoxy-3,5-O-[(4-methoxyphenyl)methylene]-2,4-dimethyl-L-arabinose(23.2 g, 87.88 mmol) in 50 mL of THF is added dropwise over 30 min at−70° C. to −74° C. The resultant solution is stirred at that temperaturerange for 1.5 h and then warmed to 0° C. The reaction is quenched with 6mL of water in 90 mL of THF, 6 mL of 15% NaOH, and 30 mL of water at 0°C. to 10° C. The organic phase is separated and the aqueous phase isextracted with ethyl acetate (3×200 mL). The combined organic layers arewashed with water (2×300 mL), brine (2×300 mL), dried over Na₂SO₄ andconcentrated. The desired product (24.6 g, 105%) is obtained as a clearoil.

[0237]¹H NMR (300 MHz, CDCL₃), δ 7.38 (d, J=8.7 Hz, 2H), 6.88 (d, J=8.7Hz, 2H), 5.48 (s, 1H), 4.11 (m, 1H), 3.8-3.65 (m, 3H), 3.80 (s, 3H),3.52 (apparent t, J=11.3 Hz, 1H), 2.17-1.92 (m, 3H), 1.05 (d, J=7.16 Hz,3H), 0.77 (d, J=6.8 Hz, 3H); ¹³C NMR (CDCl₃, 75 MHz), δ 159.9, 131.1,127.3, 121.3, 113.6, 101.1, 84.7, 73.2, 66.8, 55.3, 35.6, 30.4, 11.9,9.72.

[0238] c) Preparation of2,4-dideoxy-1-O-[(1,1-dimethylethyl)dimethylsilyl]-3,5-O-[(4-methoxyphenyl)methylene]-2,4-dimethyl-L-arabinitol.

[0239] A solution of2,4-dideoxy-3,5-O-[(4-methoxyphenyl)methylene]-2,4-dimethyl-L-arabinitol(24.5 g, 92.48 mmol), 2,6-lutidine (17.84 g, 166.46 mmol) and methylenechloride (400 mL) is cooled to −20° C. TBSOTf (36.67 g, 138.72 mmol) isadded over 30 min. After stirring for an additional 2 h at 0° C., themixture is diluted with ether (400 mL), washed with aqueous NaHSO₄,brine, and concentrated. Flash chromatography affords the desiredproduct (30 g, 86%) as a white solid.

[0240]¹H NMR (300 MHz, CDCl₃), δ 7.37 d, J=8.7 Hz, 2H), 6.85 (d, J=8.7Hz, 2H), 5.38 (s, 1H), 4.10 (dd, J=11.3, 4.9, 1H), 3.77 (s, 3H),3.66-3.60 (m, 2H), 3.51-3.44 (m, 2H), 2.07-1.88 (m, 2H), 0.90 (d, J=7.54Hz, 3H), 0.87 (s, 9H), 0.72 (d, J=6.8 Hz, 3H), 0.004 (s, 6H); ¹³C NMR(CDCl₃, 75 MHz), δ 159.7, 131.6, 127.3, 121.3, 113.4, 100.9, 81.4, 73.3,64.8, 55.3, 36.6, 30.3, 26.0, 18.3, 12.1, 9.73, −5.33, −5.36.

[0241] d) Preparation of2,4-dideoxy-1-O-[(1,1-dimethylethyl)dimethylsilyl]-3-O-[(4-methoxyphenyl)methyl]-2,4-dimethyl-L-arabinitol.

[0242] A solution of2,4-dideoxy-1-O-[(1,1-dimethylethyl)dimethylsilyl]-3,5-O-[(4-methoxyphenyl)methylene]-2,4-dimethyl-L-arabinitol(29 g, 76.3 mmol) and methylene chloride (500 mL) is cooled to −73° C.,and DIBAL (1.0 M in hexane, 763 mL, 763 mmol) is added dropwise over 1.5h. After 1 additional hour at −78° C., the reaction mixture is warmed to0° C. The reaction is quenched very slowly with saturated Rochelle'ssalt. The solution is separated. The aqueous phase is extracted withethyl acetate (2×200 mL). The combined organic phase is washed withbrine (2×200 mL), and concentrated. Flash chromatography affords thedesired product (24.5 g, 84%) as a clear oil.

[0243]¹H NMR (300 MHz, CDCl₃), δ 7.22 (d, J=7.9 Hz, 2H), 6.82 (d, J=8.7Hz, 2H), 4.50(dd, J=26.4, 10.9, 2H), 3.74 (s, 3H), 3.59-3.44 (m, 5H),2.75 (apparent t, J=5.80, 1H), 1.92-1.76 (m, 1H), 0.87-0.84 (m, 3H),0.85 (s, 9H), 0.825 (d, J=1.9 Hz, 3H), 0.00 (s, 6H); ¹³C NMR (CDCl₃, 75MHz), δ 159.3, 130.7, 129.5, 113.9, 83.6, 74.6, 67.0, 65.6, 55.3, 38.6,37.8, 25.9, 18.2, 14.9, 10.7, −5.31, −5.38.

[0244] e) Preparation of2,4-dideoxy-5-O-[(1,1-dimethylethyl)dimethylsilyl]-3-O-[(4-methoxyphenyl)methyl]-2,4-dimethyl-L-lyxose.

[0245] A solution of2,4-dideoxy-1-O-[(1,1-dimethylethyl)dimethylsilyl]-3-O-[(4-methoxyphenyl)methyl]-2,4-dimethyl-L-arabinitol(10.77 g, 28.19 mmol), DMSO (30 mL), NEt₃ (11.39 g, 112.76 mmol) andmethylene chloride is cooled to −10° C., and treated with SO₃-Pyr (13.45g, 84.58 mmol)in DMSO (60 mL) over 40 min. After additional 2 h at 0°C., the mixture is diluted with ether (300 mL), washed with 1 M aqueousNaHSO₄ (100 mL), brine (100 mL), and concentrated. Flash chromatography(5% ethyl acetate in hexane) gives the desired compound (9 g, 84%) as acolorless oil.

[0246]¹H NMR (300 MHz, CDCl₃), δ 9.70 (d, J=2.26 Hz, 1H),

d, J=8.3 Hz, 2H), 6.81 (d, J=8.3 Hz, 2H), 4.45 (dd, J=20.7, 10.9 Hz,2H), 3.79 (dd, J=7.91, 3.76, 1H), 3.74 (s, 3H), 3.56-3.44 (m, 2H),2.71-2.59 (m, 1H), 1.89-1.76 (m, 1H), 0.98 (d, J=7.16 Hz, 3H), 0.86 (d,J=8 Hz, 3H), 0.85 (s, 9H), 0.002 (s, 6H); ¹³C NMR (CDCl₃, 75 MHz), δ204.9, 159.2, 130.7, 129.3, 113.8, 79.8, 74.0, 65.0, 55.3, 49.3, 38.4,25.9, 18.2, 11.23, 10.98, −5.35, −5.41.

[0247] f) Preparation of the(1,1-dimethylethyl)[[(2S,3S,4S,5Z)-3-[(4-methoxyphenyl)methoxy]-2,4-dimethyl-5,7-octadienyl]oxy]dimethyl-silane.

[0248] A suspension consisting of CrCl₂ (12.93 g, 105.38 mmol) and 700mL anhydrous THF is cooled to 0° C.2,4-dideoxy-5-O-[(1,1-dimethylethyl)dimethylsilyl]-3-O-[(4-methoxyphenyl)methyl]-2,4-dimethyl-L-lyxose(8.9 g, 23.42 mmol) in 40 mL THF is added dropwise. (1-Bromoallyl)trimethylsilane (22.61, 117.1 mmol) is added neat. After 3 h at roomtemperature, the reaction mixture is cooled to 10° C. Methanol (270 mL)and 6 N aqueous KOH (550 mL) are added in sequence, keeping the reactiontemperature less than 20° C. during the addition. The mixture is stirredovernight at room temperature. The organic layer is separated. Theaqueous layer is extracted with ether (3×400 mL). The combined organicphase is washed with brine, dried over NaSO₄, and concentrated. Flashchromatography gives the desired compound (6.74 g, 71.2%) as a clearoil.

[0249]¹H NMR (300 MHz, CDCl₃), δ 7.20 (d, J=8.7 Hz, 2H), 6.81 (d, J=8.7Hz, 2H), 6.61 (dt, J=16.96, 10.92 Hz, 1H), 5.97 (t, J=10.92 Hz, 1H),5.46 (t, J=10.55 Hz, 1H), 5.09 (dd, J=33.5, 17.0 Hz, 2H), 4.45 (dd,J=27.5, 9.4 Hz, 2H), 3.76 (s, 3H), 3.51-3.32 (m, 3H), 2.97-2.82 (m, 1H),1.85-1.76 (m, 1H), 0.97 (d, J=7.16 Hz, 3H), 0.88 (d, J=7.9 Hz, 3H), 0.87(s, 9H), 0.001 (s, 6H); ¹³C NMR (CDCl3, 75 MHz), δ 161.79, 138.13,134.77, 131.52, 131.07, 119.22, 115.79, 85.2, 76.6, 67.8, 57.5, 40.9,37.8, 28.2, 20.6, 13.8, −3.13, −3.15.

[0250] g) Preparation of(2S,3S,4S,5Z)-3-[(4-methoxyphenyl)methoxy]-2,4-dimethyl-5,7-octadien-1-ol.

[0251] A solution of(1,1-dimethylethyl)[[(2S,3S,4S,5Z)-3-[(4-methoxyphenyl)methoxy]-2,4-dimethyl-5,7-octadienyl]oxy]dimethylsilane(6.74 g, 16.68 mmol) and THF (70 mL) is cooled to 0° C. 4 N aqueous HCl(70 mL) is added to the solution dropwise to maintain the reactiontemperature at less than 5° C. The mixture is stirred at 0° C. for 1 h.The mixture is quenched by the addition of saturated aqueous NaCO₃. Theorganic phase is separated. The aqueous phase is extracted with ethylacetate (5×100 mL). The combined organic phase is washed with brine,dried over NaSO₄ and concentrated. Flash chromatography gives thedesired compound (4.17 g, 86%) as a clear oil.

[0252]¹H NMR (300 MHz, CDCl3), δ 7.25 (d, J=8.7 Hz, 2H), 6.86 (d, J=8.7Hz, 2H), 6.67 (dt, J=21.5, 11.3 Hz, 1H), 6.04 (t, J=11.31 Hz, 1H), 5.55(t, J=10.55 Hz, 1H), 5.16 (dd, J=34.3, 16.95 Hz, 2H), 4.53 (dd, J=36.6,10.9, 2H), 3.80 (s, 3H), 3.65-3.49 (m, 2H), 3.40 (dd, J=5.7, 3.8 Hz,1H), 3.05-2.95 (m, 1H), 2.03-1.90 (m, 1H), 1.83 (t, J=5.7 Hz, 1H), 1.02(d, J=6.8 Hz, 3H), 0.95 (d, J=6.8 Hz, 3H); ¹³C NMR (CDCl₃, 75 MHz), δ159.2, 135.4, 132.5, 130.8, 129.6, 129.1, 117.5, 113.7, 84.2, 73.9,66.1, 55.3, 37.7, 35.1, 18.6, 11.5.

[0253] h) Preparation of(2R,3S,4S,5Z)-3-[(4-methoxyphenyl)methoxy]-2,4-dimethyl-5,7-octadienal.

[0254] A solution of(2S,3S,4S,5Z)-3-[(4-methoxyphenyl)methoxy]-2,4-dimethyl-5,7-octadien-1-ol(2.0 g, 6.9 mmol), DMSO (2.1 mL), NEt₃ (2.79 g, 27.59 mmol) andmethylene chloride (20 mL) is cooled to 0° C., and is treated withSO₃-Pyr (3.29 g, 20.69 mmol) and DMSO (8 mL) over 10 min. Afteradditional 2 h at 0° C., the mixture is diluted with ether (200 mL),washed with 1 M aqueous NaHSO₄ (100 mL), brine (100 mL), andconcentrated. Flash chromatography (1% to 10% ethyl acetate in hexane)gives the desired compound (1.95 g, 98.2%) as a colorless oil.

[0255]¹H NMR (300 MHz, CDCl₃), δ 9.69 (d, J=1.1 Hz, 1H),

d, J=8.7 Hz, 2H), 6.86 (d, J=8.7 Hz, 2H), 6.55 (dt, J=17.0, 10.2 Hz,1H), 6.05 (t, J=10.9 Hz, 1H), 5.45 (t, J=10.55 Hz, 1H), 5.16 (dd,J=30.9, 16.95 Hz, 2H), 4.475 (dd, J=18.5, 10.9, 2H), 3.80 (s, 3H), 3.71(t, J=4.9 Hz, 1H), 3.03-2.90 (m, 1H), 2.64-2.55 (m, 1H), 1.16 (d, J=7.2Hz, 3H), 1.06 (d, J=6.9 Hz, 3H); ¹³C NMR (CDCl₃, 75 MHz), δ 204.2,159.2, 133.8, 132.1, 130.3, 130.1, 129.4, 118.1, 113.7, 81.9, 73.6,55.3, 49.5, 35.5, 18.3, 9.2.

[0256] i) Preparation of(4R)-3-[(2R,3S,4S,5S,6S,7Z)-3-hydroxy-5-[(4-methoxyphenyl)methoxy]-2,4,6-trimethyl-1-oxo-7,9-decadienyl]-4-(phenylmethyl)-2-oxazolidinone.

[0257] A solution of (R)-4-benzyl-3-propionyl-2-oxazolidinone (2.18 g,9.34 mmol) and methylene chloride (15 mL) is cooled to −20° C.(n-Bu)₂BOTf (1.0 M in DCM, 8.7 mL, 8.7 mmol) is introduced dropwise. Thereaction is allowed to warm to 0° C. NEt₃ (1.15 g, 11.34 mmol) is addedand the mixture is stirred at 0° C. for 1 h, then cooled to −78° C. Asolution of(2R,3S,4S,5Z)-3-[(4-methoxyphenyl)methoxy]-2,4-dimethyl-5,7-octadienal(1.95 g, 6.77 mmol) in DCM (10 mL) is added dropwise at −70° C. for 10min. After 1 h at −74° C., the mixture is warmed to 0° C. The reactionis quenched with pH 7 buffer (15 mL). The mixture is slowly treated witha solution of 30% H₂O₂ in MeOH (1:2, 15 mL) at 0° C., stirred for 40 minat room temperature, and concentrated. The residue is extracted withethyl acetate (3×100 mL). The combined organic phase is washed withsaturated aqueous NaHCO₃, brine, and concentrated. Flash chromatographygives the desired compound (3.4 g, 96.4%) as a clear oil.

[0258]¹H NMR (300 MHz, CDCl₃), δ 7.38-7.16 (m, 7H), 6.82 (d, J=8.7 Hz,2H), 6.69 (dt, J=17.0, 10.2 Hz, 1H), 6.06 (t, J=11.3 Hz, 1H), 5.50 (t,J=10.55 Hz, 1H), 5.17 (dd, J=30.1, 16.95, Hz, 2H), 4.53 (dd, J=98.7,10.9, 2H), 4.63-4.56 (m, 1H), 4.23-4.10 (m, 2H), 4.02-3.96 (m, 1H), 3.83(t, J=6.4 Hz, 1H), 3.78 (s, 3H), 3.38-3.33(m, 1H), 3.25-3.15 (m, 2H),3.07-2.95 (m, 1H), 2.74 (dd, J=13.6, 9.8 Hz, 1H), 1.84-1.73 (m, 1H),1.29 (d, J=7.2 Hz, 3H), 1.02 (d, J=6.8 Hz, 3H), 0.98 (d, J=6.8 Hz, 3H);¹³C NMR (CDCl₃, 75 MHz), δ 176.8, 159.0, 152.7, 135.6, 135.1, 132.5,130.7, 129.5, 129.4, 129.3, 128.9, 127.4, 117.7, 113.6, 86.3, 74.3,73.8, 66.0, 55.3, 55.0, 40.6, 37.8, 37.7, 35.8, 18.14, 13.28.

[0259] j) Preparation of((4R)-3-[(2R,3S,4R,5S,6S,7Z)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-5-[(4-methoxyphenyl)methoxy]-2,4,6-trimethyl-1-oxo-7,9-decadienyl]-4-(phenylmethyl)-2-oxazolidinone.

[0260] A solution of(4R)-3-[(2R,3S,4S,5S,6S,7Z)-3-hydroxy-5-[(4-methoxyphenyl)methoxy]-2,4,6-trimethyl-1-oxo-7,9-decadienyl]-4-(phenylmethyl)-2-oxazolidinone(3.4 g, 6.53 mmol), 2,6-lutidine (3.5 g, 32.65 mmol) and methylenechloride (100 mL) is cooled to 0° C. TBSOTf (7.12 g, 26.94 mmol)is addedover 30 min and the resultant mixture is allowed to react overnight at0° C. The mixture is diluted with ether (300 mL), washed with aqueousNaHSO₄, brine, and concentrated. Flash chromatography affords thedesired compound (3.6 g, 87%) as an oil.

[0261]¹H NMR (300 MHz, CDCl₃), δ 7.25-7.05 (m, 7H), 6.74 (d, J=8.7 Hz,2H), 6.58 (dt, J=16.5, 10.2 Hz, 1H), 5.86 (t, J=11.3 Hz, 1H), 5.49 (t,J=10.55 Hz, 1H), 5.10-5.01(m, 3H), 4.44-4.38 (m, 1H), 4.41 (s, 2H),4.00-3.87 (m, 4H), 3.69 (s, 3H), 3.26 (dd, J=7.5, 3 Hz, 1H), 2.96-2.84(m, 1H), 2.59 (dd, J=13.6, 9.8 Hz, 1H), 1.56-1.46 (m, 1H), 1.13(d, J=6.4Hz, 3H), 1.01 (d, J=7.2 Hz, 3H), 0.92 (d, J=7.2 Hz, 3H), 0.86 (s, 9H),0.035 (d, J=6.4 Hz, 6H); ¹³C NMR (CDCl₃, 75 MHz), δ 175.7, 158.9, 152.8,135.4, 134.3, 133.1, 131.3, 129.5, 129.4, 129.0, 128.9, 127.3, 116.8,113.6, 82.9, 74.5, 73.6, 65.9, 55.5, 55.3, 43.1, 42.1, 37.7, 35.6, 26.3,25.7, 19.1, 18.5, 14.9, 10.27, −3.4, −3.6.

[0262] k) Preparation of(2R,3S,4R,5S,6S,7Z)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-5-[(4-methoxyphenyl)methoxy]-2,4,6-trimethyl-7,9-decadienoicacid.

[0263] A solution of(4R)-3-[(2R,3S,4R,5S,6S,7Z)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-5-[(4-methoxyphenyl)methoxy]-2,4,6-trimethyl-1-oxo-7,9-decadienyl]-4-(phenylmethyl)-2-oxazolidinone),THF (15 mL) and water (5 mL) is cooled to 10° C. Hydrogen peroxide (50%,20 mL) is added dropwise, followed by the addition of LiOH (0.575 g).The mixture is stored at 10° C. overnight. The reaction is quenched withthe addition of saturated aqueous Na₂SO₃. The mixture is acidified bythe addition aqueous HCl (12 M) to pH 1, then is extracted with ether.The combined organic phase is washed with brine, dried over Na2SO4, andconcentrated. Flash chromatography gives the desired compound (1.34 g,83%) as a white solid.

[0264] δ 7.26 (d, J=8.7, 2H), 6.85 (d, J=8.7 Hz, 2H), 6.69 (dt, J=17.0,10.9 Hz, 1H), 6.02 (t, J=11.3 Hz, 1H), 5.50 (t, J=10.55 Hz, 1H), 5.21(d, J=16.5 Hz, 1H), 5.12 (d, J=10.2 Hz, 1H), 4.50 (dd, J=29.4, 10.2 Hz,2H), 4.07 (t, J=4.5 Hz, 1H), 3.79 (s, 3H), 3.25 (t, J=5.3 Hz, 1H),3.05-2.94 (m, 1H), 2.74-2.65 (m, 1H), 1.90-1.79 (m, 1H), 1.11 (d, J=7.2Hz, 3H), 1.06 (d, J=6.8 Hz, 3H), 1.00 (d, J=6.8 Hz, 3H), 0.93 (s, 9H),0.10 (d, J=7.9 Hz, 6H); ¹³C NMR (CDCl₃, 75 MHz), δ 238.3, 159.1, 134.4,132.3, 130.8, 129.5, 117.7, 113.7, 83.3, 74.6, 74.1, 55.3, 43.5, 40.3,35.5, 26.0, 18.5, 18.3, 11.6, 10.4, −4.05.

[0265] l) Preparation of1,2,4-trideoxy-3-O-[(1,1-dimethylethyl)dimethylsilyl]-1-[[(2R,3S,4R,5S,6S,7Z)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-5-[(4-methoxyphenyl)methoxy]-2,4,6-trimethyl-1-oxo-7,9-decadienyl]methylamino]-5-O-[(4-methoxyphenyl)methyl]-2,4-dimethyl-L-arabinitol.

[0266] To a solution of1,2,4-trideoxy-3-O-[(1,1-dimethylethyl)dimethylsilyl]-5-O-[(4-methoxyphenyl)methyl]-2,4-dimethyl-1-(methylamino)-L-arabinitol(1.23 g, 3.1 mmol) and(2R,3S,4R,5S,6S,7Z)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-5-[(4-methoxyphenyl)methoxy]-2,4,6-trimethyl-7,9-decadienoicacid (1.14 g, 2.4 mmol) in DMF (20 mL) at room temperature,benzotriazol-1-yl-oxyl-tris(dimethyamino)phosphonium hexafluorophosphate(BOP) (2.12 g, 4.8 mmol) and DIEA (1.86 g, 14.4 mmol) are added. Afterbeing stirred at room temperature overnight, the reaction mixture ispurified by column chromatography on silica gel with hexane/EtOAc(90/10) to give the desired product (1.93 g, 94.5%) as a pale viscousoil.

[0267]¹H NMR (CDCl₃, 300 MHz), δ 7.22-7.17 (m, 4H), 6.83-6.76 (m, 4H),6.70-6.59 (m, 1H), 5.96 (t, J=10.20 Hz, 1H), 5.58-5.45 (m, 1H),5.16-5.05 (m, 2H), 4.57-4.46 (m, 1H), 4.35-4.34 (m, 2H), 4.16 (dd,J=9.04, 4.90 Hz, 1H), 3.75(s, 3H), 3.74 (s, 3H), 3.54 (t, J=5.65 Hz,1H), 3.47-3.39 (m, 3H), 3.25-3.17 (m, 2H), 3.14-3.03 (m, 1H), 3.00-2.90(m, 2H), 2.55 (s, 3H), 1.94-1.81 (m, 2H), 1.78-1.73 (m, 1H), 1.06 (t,J=6.03 Hz, 3H), 0.99 (d, J=7.16 Hz, 3H), 0.95-0.88 (m, 12H), 0.85-0.81(m, 12H), 0.72 (d, J=6.78 Hz, 3H), 0.11 (s, 3H), 0.06 (s, 3H), 0.00 (s,3H), −0.04 (s, 3H); ¹³C NMR (CDCl₃, 300 MHz), δ 176.3, 159.0, 158.9,135.1, 133.2, 131.3, 130.9, 129.3, 129.2, 129.1, 116.9, 113.7, 113.5,81.8, 75.8, 74.4, 73.7, 72.6, 72.6, 55.3, 40.9, 38.6, 38.5, 35.8, 35.7,34.9, 29.7, 26.3, 26.1, 26.0, 18.5, 18.4, 18.4, 16.1, 15.0, 12.5, 8.6,−3.7, −3.7, −3.9, −4.2.

[0268] m) Preparation of1,2,4-trideoxy-3-O-[(1,1-dimethylethyl)dimethylsilyl]-1-[[(2R,3S,4R,5S,6S,7Z)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-5-hydroxy-2,4,6-trimethyl-1-oxo-7,9-decadienyl]methylamino]-2,4-dimethyl-L-arabinitol.

[0269] To a solution consisting of1,2,4-trideoxy-3-O-[(1,1-dimethylethyl)dimethylsilyl]-1-[[(2R,3S,4R,5S,6S,7Z)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-5-[(4-methoxyphenyl)methoxy]-2,4,6-trimethyl-1-oxo-7,9-decadienyl]methylamino]-5-O-[(4-methoxyphenyl)methyl]-2,4-dimethyl-L-arabinitol(1.9 g, 2.2 mmol), CH₂Cl₂ (40 mL), and H₂O (1 mL) at room temperature,is added 2,3-dichloro-5,6-Dicyano-1,4-benzoquinone (DDQ), (2.53 g, 11.1mmol). After stirring at room temperature for 10 min, the reactionmixture is purified by column chromatography on silica gel withhexane/EtOAc (90/10) to give the desired product (1.15 g, 82.6%) as awhite solid.

[0270]¹H NMR (CDCl₃, 500 MHz), δ 6.57-6.45 (m, 1H), 6.03 (t, J=11.24 Hz,1H), 5.20 (d, J=10.93 Hz, 1H), 5.13 (d, J=16.95 Hz, 1H), 5.03 (d, J=9.78Hz, 1H), 4.04-3.91 (m, 1H), 3.54-3.45 (m, 4H), 3.22-3.16 (m, 1H), 3.07(t, J=7.16 Hz, 1H), 2.93 (s, 3H), 2.67-2.59 (m, 1H), 2.45 (s, 1H),2.10-1.96 (m, 1H), 1.80-1.72 (m, 1H), 1.52 (s, 1H), 0.98 (d, J=7.16 Hz3H), 0.96 (d, J=7.16 Hz, 3H), 0.84 (d, J=6.77 Hz, 3H), 0.83-0.77 (m,21H), 0.01 (s, 3H), 0.00 (s, 3H), 0.00 (s, 3H), −0.01 (s, 3H); ¹³C NMR(CDCl₃, 125 MHz), δ 176.3, 135.1, 132.2, 131.1, 118.2, 78.4, 76.2, 73.7,65.7, 52.6, 40.3, 39.2, 37.0, 36.5, 36.2, 26.1, 26.1, 26.0, 18.25, 17.6,17.3, 15.9, 15.5, 13.4, 9.0, −3.8, −3.9, −4.0, −4.1.

[0271] n) Preparation of1,2,4-trideoxy-3-O-[(1,1-dimethylethyl)dimethylsilyl]-1-[[(2R,3S,4R,5S,6S,7Z)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-5-hydroxy-2,4,6-trimethyl-1-oxo-7,9-decadienyl]methylamino]-2,4-dimethyl-L-arabinitol.

[0272] To a solution consisting of1,2,4-trideoxy-3-O-[(1,1-dimethylethyl)dimethylsilyl]-1-[[(2R,3S,4R,5S,6S,7Z)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-5-hydroxy-2,4,6-trimethyl-1-oxo-7,9-decadienyl]methylamino]-2,4-dimethyl-L-arabinitol(1.8 g, 2.94 mmol), 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) (86 mg,0.57 mmol), and CH₂Cl₂ (10 mL) at room temperature, is added iodobenzenediacetate (BAIB) (1.13 g, 3.51 mmol). The mixture is stirred at roomtemperature until TLC (hexane-EtOAc 95:5) indicates total consumption ofthe starting material. The mixture is diluted with CH₂Cl₂ (10 mL), andwashed sequentially with saturated Na₂S₂O₃ (20 mL), 1 M NaHCO₃ (20 mL),then brine (20 mL). The solution is dried (Na₂SO₄) and concentrated invacuo. The desired product (2.44 g) is obtained as an oil and is used inthe next step without further purification.

[0273]¹H NMR (CDCl₃, 300 MHz), δ 9.62 (d, J=2.62 Hz, 1H), 6.52 (td,J=10.93, 16.95 Hz, 1H), 6.03 (t, J=10.92 Hz, 1H), 5.25-5.02 (m, 3H),4.03 (q, J=3.76 Hz, 1H), 3.72 (q, J=5.65 Hz, 1H), 3.46 (d, J=7.91 Hz,1H), 3.19-3.03 (m, 2H), 2.92 (s, 3H), 2.63 (q, J=7.53 Hz, 1H), 2.46 (td,J=2.63, 5.27 Hz, 1H), 2.01-1.90 (m, 1H), 1.79-1.75 (m, 1H), 1.48 (s,1H), 1.19-1.47 (m, 4H), 1.02-0.96 (m, 6H), 0.83-0.73 (m, 24H), 0.00-0.05(m, 12H); ¹³C NMR (CDCl₃, 75 MHz), δ 205.0, 176.7, 135.5, 132.6, 127.9,118.8, 74.1, 51.3, 40.7, 39.6, 37.4, 36.9, 36.7, 32.0, 26.6, 26.4, 26.3,23.1, 18.7, 18.7, 18.0, 14.3, 13.1, 12.4, 9.5, −3.4, −3.5, −3.7.

[0274] o) Preparation of(2Z,4S,5S,6S)-5-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-7-[[(2R,3S,4R,5S,6S,7Z)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-5-hydroxy-2,4,6-trimethyl-1-oxo-7,9-decadienyl]methylamino]-4,6-dimethyl-2-heptenoicacid methyl ester.

[0275] To a solution consisting ofbis(2,2,2-trifluoroethyl)-2,2,5-(methoxycarbonylmethyl)phosphonate (715mg, 2.25 mmol), 18-crown-6 (453 mg, 1.7 mmol), and toluene (5 mL) at−20° C., is slowly added a solution of potassiumbis(trimethylsilyl)amide (0.5 M in toluene, 4.5 mL, 2.25 mmol). Afterstirring at 0° C. for 20 min, the mixture is cooled to −20° C., and asolution of1,2,4-trideoxy-3-O-[(1,1-dimethylethyl)dimethylsilyl]-1-[[(2R,3S,4R,5S,6S,7Z)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-5-hydroxy-2,4,6-trimethyl-1-oxo-7,9-decadienyl]methylamino]-2,4-dimethyl-L-arabinitol(711 mg, 0.85 mmol) in toluene (3 mL) is added slowly. The mixture isstirred at 0° C. for 3 h, after which the mixture is quenched withsaturated NH₄Cl (10 mL), and extracted with EtOAc (3×20 mL). Thecombined organic layers are then dried (Na₂SO₄), concentrated, andpurified by column chromatography on silica gel with hexane/EtOAc(90/10) to give the desired compound (487 mg, 85.3%) as a thickcolorless oil.

[0276]¹H NMR (CDCl₃, 500 MHz), δ 6.60-6.47 (m, 1H), 6.31 (t, J=12.06 Hz,1H), 6.04 (t, J=10.92 Hz, 1H), 5.69 (dd, J=11.30, 3.01 Hz, 1H), 5.24 (t,J=10.55 Hz, 1H), 5.13 (d, J=7.32 Hz, 1H), 5.04 (d, J=10.17 Hz, 1H), 2H),4.05 (dd, J=8.29, 4.52 Hz, 1H), 3.93 (dd, J=8.24, 4.14 Hz, 1H), 3.60 (s,3H), 3.52 (d, J=7.91 Hz, 1H), 3.45-3.39 (m, 3H), 3.09-3.02 (m, 1H), 2.88(s, 3H), 2.71-2.61 (m, 2H), 1.89-1.76 (m, 2H), 1.60 (dd, J=14.32, 3.77Hz, 1H), 1.17 (d, J=3.01 Hz, 1H), 0.99 (d, J=7.06 Hz, 3H), 0.96 (d,J=4.14 Hz, 3H), 0.94 (d, J=4.03 Hz, 3H), 0.83 (s, 18H), 0.79-0.74 (m,6H), 0.03-0.00 (m, 12H); ¹³C NMR (CDCl₃, 500 MHz), δ 176.5, 167.0,153.0, 152.7, 131.6, 131.3, 118.8, 118.5, 78.2, 76.7, 74.3, 51.5, 51.3,40.6, 39.7, 37.4, 37.3, 37.2, 36.0, 26.5, 26.4, 18.7, 18.7, 18.6, 18.0,14.5, 13.8, 9.2, −3.2, −3.4, −3.5, −3.6.

[0277] p) Preparation of(2Z,4S,5S,6S)-7-[[(2R,3S,4R,5S,6S,7Z)-5-[(aminocarbonyl)oxy]-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-2,4,6-trimethyl-1-oxo-7,9-decadienyl]methylamino]-5-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4,6-dimethyl-2-heptenoicacid methyl ester.

[0278] To a solution of(2Z,4S,5S,6S)-5-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-7-[[(2R,3S,4R,5S,6S,7Z)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-5-hydroxy-2,4,6-trimethyl-1-oxo-7,9-decadienyl]methylamino]-4,6-dimethyl-2-heptenoicacid methyl ester (1.8 g, 2.7 mmol) in CH₂Cl₂ (10 mL) at roomtemperature, is added trichloroacetyl isocyanate (763 mg, 4.05 mmol) inone portion. The mixture is stirred at room temperature for 1 h, andconcentrated in vacuo. The residue is dissolved in MeOH (10 mL), andthen K₂CO₃ (0.4 g) is added. After stirring at room temperature for 2 h,the mixture is concentrated in vacuo, then purified by columnchromatography with silica gel eluted with hexane/EtOAc (70/30) to givethe desired compound (1.77 g, 92.4%) as a colorless glassy solid.

[0279]¹H NMR (CDCl₃, 500 MHz), δ 6.65 (td, J=10.87, 16.71 Hz, 1H),6.46-6.36 (m, 1H), 6.01 (t, J=10.87 Hz, 1H), 5.80 (dd, J=11.67, 8.04 Hz,1H), 5.42 (q, J=11.11 Hz, 1H), 5.21-5.51 (m, 2H), 4.94 (t, J=5.51 Hz,1H), 4.83 (dd, J=8.51, 3.46 Hz, 1H), 4.60 (s, 1H), 4.52 (s, 1H), 4.08(dd, J=7.88, 3.15 Hz, 1H), 3.97 (dd, J=7.56, 1.42 Hz, 1H), 3.71 (s, 3H),3.58-3.57 (m, 1H), 3.54 (t, J=3.63 Hz, 1H), 3.42-3.31 (m, 2H), 3.16-3.09(m, 1H), 3.01-2.96 (m, 1H), 2.93 (s, 1H), 2.87 (t, J=7.10 Hz, 1H),2.79-2.75 (m, 1H), 2.71 (s, 1H), 1.95-1.87 (m, 1H), 1.09 (d, J=3.62 Hz,3H), 1.08 (d, J=3.74 Hz, 3H), 1.05 (d, J=8.36 Hz, 3H), 1.10 (d, J=6.94Hz, 3H), 0.94 (s, 18H), 0.86 (d, J=7.25 Hz, 3H), 0.83 (d, J=6.94 Hz,3H), 0.12 (s, 3H), 0.12 (s, 3H), 0.11 (s, 3H), 0.11 (s, 3H); ¹³C NMR(CDCl₃, 500 MHz), δ 175.8, 167.1, 157.3, 153.1, 133.4, 133.0, 130.7,118.9, 117.8, 78.7, 77.7, 74.5, 51.6, 51.5, 41.0, 40.1, 38.7, 37.4,37.3, 36.2, 35.8, 26.6, 26.5, 18.9, 18.8, 18.5, 14.4, 13.9, 10.6, −3.1,−3.4, −3.6.

[0280] q) Preparation of(2R,3S,4R,5S,6S,7Z)-5-[(aminocarbonyl)oxy]-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-N-[(2S,3S,4S,5Z)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-7-hydroxy-2,4-dimethyl-5-heptenyl]-N,2,4,6-tetramethyl-7,9-decadienamide.

[0281] To a solution of(2Z,4S,5S,6S)-7-[[(2R,3S,4R,5S,6S,7Z)-5-[(aminocarbonyl)oxy]-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-2,4,6-trimethyl-1-oxo-7,9-decadienyl]methylamino]-5-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4,6-dimethyl-2-heptenoicacid methyl ester (1.77 g, 2.5 mmol) and CH₂Cl₂ (15 mL) cooled to −78°C., was added a solution consisting of diisobutylaluminum hydride (1.0 Min hexane, 7.5 mL, 7.5 mmol). After stirring at −40° C. for 4 h, themixture is quenched by adding saturated potassium sodium tartrate (10mL). The mixture is then extracted with CH₂Cl₂ (3×20 mL). The combinedorganic layers are then dried (Na₂SO₄), concentrated in vacuo, andchromatographed using silica gel eluted with hexane/EtOAc (70/30) togive the desired compound (1.04 mg, 61.4%) as a colorless glassy solid.

[0282]¹H NMR (CDCl₃, 500 MHz), δ 6.68-6.60 (m, 1H), 6.06-6.01 (m, 1H),5.67-5.60 (m, 2H), 5.42 (t, J=9.77 Hz, 1H), 5.22 (d, J=6.86 Hz, 1H),5.13 (d, J=5.83 Hz, 1H), 4.94 (t, J=5.83 Hz, 1H), 4.47 (s, 1H),4.41-4.36 (m, 2H), 4.06 (dd, J=7.41, 3.47 Hz, 1H), 4.01-3.96 (m, 1H),3.69 (dd, J=13.24, 11.83 Hz, 1H), 3.53 (dd, J=8.82, 4.25 Hz, 1H), 3.48(dd, J=5.36, 2.36 Hz, 1H), 3.07 (dd, J=13.04, 4.25 Hz, 1H), 3.00-2.97(m, 1H), 2.95 (s, 3H), 2.89-2.81 (m, 2H), 2.06-2.01 (m, 1H), 1.94-1.91(m, 1H), 1.07 (d, J=6.94 Hz, 3H), 1.01 (d, J=6.78 Hz, 3H), 0.99 (d,J=6.94 Hz, 3H), 0.94 (s, 18H), 0.86 (d, J=7.25 Hz, 3H), 0.85 (d, J=7.05Hz, 3H), 0.13 (s, 3H), 0.11 (s, 3H), 0.09 (s, 6H); ¹³C NMR (CDCl₃, 125MHz), δ 176.2, 157.2, 134.9, 133.5, 132.9, 130.6, 128.7, 118.0, 79.3,77.7, 74.4, 58.9, 50.4, 40.6, 40.0, 37.8, 37.7, 36.0, 35.9, 35.1, 34.3,26.6, 26.5, 21.0, 18.4, 15.9, 14.7, 13.6, 10.7, −3.4, −3.5, −3.8.

[0283] r) Preparation of(2R,3S,4R,5S,6S,7Z)-5-[(aminocarbonyl)oxy]-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-N-[(2S,3S,4S,5Z)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-2,4-dimethyl-7-oxo-5-heptenyl]-N,2,4,6-tetramethyl-7,9-decadienamide.

[0284] To a solution of Dess-Martin periodinane (199 mg, 0.47 mmol) andCH₂Cl₂ (4 mL) at room temperature, is added a solution of(2R,3S,4R,5S,6S,7Z)-5-[(aminocarbonyl)oxy]-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-N-[(2S,3S,4S,5Z)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-7-hydroxy-2,4-dimethyl-5-heptenyl]-N,2,4,6-tetramethyl-7,9-decadienamide(200 mg, 0.29 mmol) and CH₂Cl₂ (1 mL). After stirring at roomtemperature for 1 h, the mixture is quenched by adding saturated NaHCO₃(1 mL) followed by saturated Na₂S₂O₃ (1 mL). This mixture is thenstirred at room temperature for 30 min, and then extracted with CH₂Cl₂(4×10 mL). The combined organic layers are then dried (Na₂SO₄),concentrated in vacuo, and then chromatographed (silica gel eluted withhexane/EtOAc 90/10) to give the desired compound (150 mg, 75.2%) as acolorless glassy solid.

[0285]¹H NMR (CDCl₃, 300 MHz), δ 6.61-6.47 (m, 2H), 5.94-5.83 (m, 1H),5.30 (t, J=9.80 Hz, 1H), 5.11-5.00 (m, 2H), 4.81 (t, J=5.66 Hz, 1H),4.49 (s, 1H), 3.95 (dd, J=7.54, 3.02 Hz, 1H), 3.44 (t, J=3.76 Hz, 1H),3.16-3.11 (m, 1H), 2.88 (m, 1H), 2.86 (s, 3H), 2.77 (t, 2.77 Hz, 1H),2.64 (s, 1H), 1.94-1.72 (m, 2H), 1.20-1.13 (m, 2H), 1.05-0.97 (m, 6H),0.89 (d, J=6.78 Hz, 3H), 0.83 (s, 9H), 0.81 (s, 9H), 0.78-0.74 (m, 6H),0.03 (s, 3H), 0.01 (s, 3H), 0.00 (s, 3H), −0.04 (s, 3H); ¹³C NMR (CDCl₃,75 MHz), δ 191.5, 175.8, 157.3, 155.9, 133.4, 133.0, 129.9, 117.8, 78.0,77.7, 74.3, 52.6, 40.1, 37.4, 37.0, 36.8, 35.7, 26.6, 26.5, 26.5, 19.9,18.8, 18.6, 15.8, 13.3, 10.6, −3.1, −3.2, −3.4, −3.4.

[0286] s) Preparation of(2R,3S,4R,7S,8Z,10S,11S,12S)-13-[[(2R,3S,4R,5S,6S,7Z)-5-[(aminocarbonyl)oxy]-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-2,4,6-trimethyl-1-oxo-7,9-decadienyl]methylamino]-3,11-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-7-hydroxy-N-methoxy-N,2,4,10,12-pentamethyl-5-oxo-8-tridecenamide.

[0287] To a solution of (+)-β-chlorodiisopinocampheylborane (502 mg,1.52 mmol) and ether (1.3 mL) cooled to −6° C., is added Et₃N (0.23 mL,1.67 mmol). To this mixture is added a solution of(2R,3S,4R)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-N-methoxy-N-methyl-2,4-trimethyl-5-oxo-hexanamideand ether (1.5 mL). After stirring at 0° C. for 2 h, the mixture iscooled to −78° C. To this mixture is added a solution of(2R,3S,4R,5S,6S,7Z)-5-[(aminocarbonyl)oxy]-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-N-[(2S,3S,4S,5Z)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-2,4-dimethyl-7-oxo-5-heptenyl]-N,2,4,6-tetramethyl-7,9-decadienamide(103 mg, 0.152 mmol) and ether. The mixture is stirred at −78° C. for 3h, and then at −30° C. overnight. The reaction mixture is quenched bythe sequential addition of MeOH (4 mL), a phosphate buffer (pH=7, 1.5mL), then H₂O₂ (30%, 1.0 mL) at −78° C. The mixture is warmed to roomtemperature and stirred for 2 h. The mixture is extracted with CH₂Cl₂(4×10 mL). The combined organic layers are then dried (Na₂SO₄),concentrated in vacuo, and then chromatographed (silica gel eluted withhexane/EtOAc 80/20) to give the desired compound (123 mg, 80.3%) as acolorless glassy solid.

[0288]¹H NMR (CDCl₃, 500 MHz), δ 6.69-6.61 (m, 1H), 6.03 (t, J=11.42 Hz,1H), 5.58 (t, J=10.55 Hz, 1H), 5.44-5.40 (m, 2H), 5.22-5.19 (m, 1H),5.17-5.13 (m, 1H), 4.95 (t, J=6.06 Hz 1H), 4.84-4.80 (m, 1H), 4.66-4.45(m, 2H), 4.35 (dd, J=8.24, 4.12 Hz, 1H), 4.09 (dd, J=7.62, 3.20 Hz, 1H),3.74 (s, 3H), 3.49-3.38 (m, 3H), 3.11 (s, 3H), 3.07-3.02 (m, 1H),3.00-2.94 (m, 3H), 2.89-2.76 (m, 4H), 2.69-2.56 (m, 1H), 2.02-1.97 (M,1H), 1.91-1.88 (m, 1H), 1.72-1.66 (m, 1H), 1.27 (s, 3H), 1.15-1.11 (m,6H), 1.10-1.08 (m, 6H), 1.03-1.00 (m, 6H), 0.95 (s, 9H), 0.93 (s, 9H),0.92 (s, 9H), 0.14 (s, 3H), 0.13 (s, 3H), 0.12 (s, 3H), 0.12 (s, 3H),0.12 (s, 3H), 0.11 (s, 3H); ¹³C NMR (CDCl₃, 125 MHz), δ 212.6, 175.3,157.0, 156.8, 135.4, 133.0, 132.5, 130.1, 129.8, 117.5, 78.1, 77.2,74.1, 65.1, 61.3, 53.4, 51.8, 48.9, 40.3, 39.6, 36.8, 36.2, 35.9, 35.4,29.7, 26.2, 26.2, 26.2, 26.1, 26.1, 25.9, 25.9, 19.7, 18.5, 18.4, 18.1,15.6, 12.8, 10.2, 10.0, −3.6, −3.8, −3.8, −4.2, −4.5.

[0289] t) Preparation of(2R,3S,4S,5S,7S,8Z,10S,11S,12S)-13-[[(2R,3S,4R,5S,6S,7Z)-5-[(aminocarbonyl)oxy]-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-2,4,6-trimethyl-1-oxo-7,9-decadienyl]methylamino]-3,11-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-5,7-dihydroxy-N-methoxy-N,2,4,10,12-pentamethyl-8-tridecenamide.

[0290] Tetramethylammonium triacetoxy borohydride (182 mg, 0.69 mmol) isfirst dissolved in a mixed solution of THF/AcOH (1:1, 0.5 mL). Afterstirring at room temperature for 1 h, the mixture is cooled at −30° C.,and then a solution of(2R,3S,4R,7S,8Z,10S,11S,12S)-13-[[(2R,3S,4R,5S,6S,7Z)-5-[(aminocarbonyl)oxy]-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-2,4,6-trimethyl-1-oxo-7,9-decadienyl]methylamino]-3,11-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-7-hydroxy-N-methoxy-N,2,4,10,12-pentamethyl-5-oxo-8-tridecenamide(50 mg, 0.049 mmol) in THF/AcOH (1:1, 0.5 mL) is added slowly. Thereaction mixture is stirred at −30° C. for 3 h and at 0° C. overnight.The reaction mixture is quenched by adding saturated potassium sodiumtartrate (0.5 mL). The mixture is extracted with CH₂Cl₂ (3×10 mL). Thecombined organic layers are neutralized by adding saturated NaHCO₃,dried (Na₂SO₄), concentrated in vacuo, then chromatographed (silica geleluted with hexane/EtOAc 95/5) to give the desired compound (39.1 mg,78.4%) as a colorless glassy solid.

[0291]¹H NMR (CDCl₃, 500 MHz), δ 6.58-6.49 (m, 1H), 5.93-5.88 (m, 1H),5.40-5.30 (m, 3H), 5.10-5.01 (m, 2H), 4.81 (t, J=5.52 Hz 1H), 4.71 (dd,J=8.51, 2.84 Hz, 1H), 4.59 (s, 1H), 4.55-4.41 (m, 3H), 4.10 (d, J=9.45,1H), 3.96 (dd, J=7.56, 2.99 Hz, 1H), 3.86 (s, 1H), 3.83 (d, J=7.72 Hz,1H), 3.63 (s, 3H), 3.33 (s, 1H), 3.30-3.23 (m, 4H), 3.08 (s, 3H),3.03-2.94 (m, 2H), 2.86 (s, 3H), 2.77-2.69 (m, 2H), 2.63-2.58 (m, 2H),1.86-1.81 (m, 2H), 1.80-1.76 (m, 2H), 1.68-1.62 (m, 2H), 1.57-1.48 (m,2H), 1.43-1.39 (m, 1H), 1.07 (dd, J=6.94, 2.21 Hz, 3H), 0.98 (t, J=7.56Hz, 3H), 0.93-0.88 (m, 6H), 0.83-0.80 (m, 18H), 0.75-0.69 (m, 9H), 0.06to −0.05 (m, 18H); ¹³C NMR (CDCl₃, 125 MHz), δ 175.7, 175.6, 157.2,134.2, 133.3, 133.2, 132.9, 131.9, 130.5, 117.9, 78.2, 77.8, 74.8, 74.6,74.4, 74.2, 71.0, 66.1, 62.1, 52.8, 46.5, 40.6, 40.2, 37.7, 36.7, 35.8,33.7, 32.8, 26.6, 26.5, 26.3, 19.9, 18.9, 18.8, 18.5, 18.4, 16.4, 16.0,13.2, 12.3, 10.6, 10.4, −3.3, −3.4, −3.8, −4.1.

[0292] u) Preparation of(2R,3S,4R,5S,7S,8Z)-13-[[(2R,3S,4S,5S,6S,7Z)-5-[(aminocarbonyl)oxy]-3-hydroxy-2,4,6-trimethyl-1-oxo-7,9-decadienyl]methylamino]-3,5,7,11-tetrahydroxy-2,4,10,12-tetramethyl-8-tridecenoicacid δ-lactone

[0293](2R,3S,4S,5S,7S,8Z,10S,11S,12S)-13-[[(2R,3S,4R,5S,6S,7Z)-5-[(aminocarbonyl)oxy]-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-2,4,6-trimethyl-1-oxo-7,9-decadienyl]methylamino]-3,11-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-5,7-dihydroxy-N-methoxy-N,2,4,10,12-pentamethyl-8-tridecenamide(115 mg, 0.114 mmol) is dissolved in a solution consisting ofisopropanol (15 mL) and HCl (4 N,12 mL) at room temperature. Afterstirring at room temperature for 60 h, the mixture is cooled at −15° C.,and diluted with EtOAc (50 mL). The solution is neutralized by addingsolid NaHCO₃ in very small portions at −15° C., and is then extractedwith EtOAc (6×30 mL). The combined organic layers are dried (Na₂SO₄),concentrated in vacuo, then purified by HPLC on a reverse phase column(Nova-Pak C18, Waters) eluted with CH₃CN/H₂O (32:68) to give the desiredcompound (40.7 mg, 49.5%) as a colorless glassy solid.

[0294]¹H NMR (CDCl₃, 500 MHz), δ 6.64 (dd, J=16.86, 10.40 Hz, 1H), 6.05(t, J=10.72 Hz, 1H), 5.52 (dd, J=11.03, 7.56 Hz, 1H), 5.31-5.22 (m, 2H),5.15 (d, J=10.14 Hz, 1H), 4.90 (s, 1H), 4.76 (s, 1H), 4.66-4.62 (m, 1H),4.60 (d, J=9.62 Hz, 1H), 4.52 (m, 1H), 4.03-3.96 (m, 2H), 3.75 (s, 1H),3.63 (d, J=8.83 Hz, 1H), 3.28 (d, J=7.09 Hz, 1H), 3.07 (s, 3H), 3.02 (d,J=6.62 Hz, 1H), 2.91 (d, J=4.26 Hz, 1H), 2.83-2.78 (m, 1H), 2.69-2.61(m, 4H), 2.35 (s, 1H), 1.99-1.91 (m, 3H), 1.89-1.85 (m, 2H), 1.35 (d,J=7.26 Hz, 3H), 1.16 (d, J=7.10 Hz, 3H), 1.13 (d, J=6.77 Hz, 3H), 1.10(d, J=6.94 Hz, 3H), 1.01 (d, J=6.78 Hz, 3H), 0.94 (dd, J=10.87, 6.62 Hz,2H), 0.90 (d, J=6.47 Hz, 3H), 0.87 (d, J=6.78 Hz, 3H); ¹³C NMR (CDCl₃,500 MHz), δ 180.0, 174.5, 157.3, 135.8, 134.4, 132.7, 130.7, 118.3,73.5, 73.2, 72.7, 72.3, 65.5, 51.6, 43.5, 41.5, 36.6, 36.3, 35.6, 35.1,35.0, 33.5, 32.7, 30.1, 18.0, 17.3, 15.8, 12.8, 10.9, 10.5, 9.7.

[0295] Following are the corresponding structures of the compounds ofExamples 1 and 2:

EXAMPLE 1

[0296]

EXAMPLE 2

[0297]

What is claimed is:
 1. A compound of formula I

where A is —CH═C(R₁)CH₂—, —CH₂N(R₂)CH₂—, —CH₂N(R₂)C(O)—, —C(O)N(R₂)CH₂—,—CH₂N(CO₂R₃)CH₂— or —CH₂N(COR₂)CH₂—; B is —CH(R₁)CH═CHCH═CH₂, —CH(R₂)R₁,—CH(R₁)CH═CHR₂, —CH(R₁)CH═CHC(O)OR₂, —CH(R₁)CH═CHC(O)N(R₁)R₂,—CH(R₁)CH₂OR₂ or Ar; C is H, —C(O)N(R₁)R₂, —C(O)NHCH₂(CH₂)_(n)N(CH₃)₂,or —C(O)NHCH₂(CH₂)_(n)-4-morpholino; R₁ is H or (C₁₋₆)alkyl; R₂ is H,(C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₂₋₆)alkynyl, (C₁₋₆)alkyl-Ar or Ar; R₃ is(C₁₋₆)alkyl, (C₁₋₆)alkyl-Ar or Ar; Ar is an aromatic or heteroaromaticring selected from

R₄ and R₅ are, independently, H, (C₁₋₆)alkyl, OH, O(C₁₋₆)alkyl,OCH₂(CH₂)_(n)OH, O(CH₂)_(n)CO₂H, OCH₂(CH₂)_(n)N(CH₃)₂,OCH₂(CH₂)_(n)-4-morpholino, F, Cl, Br or CF₃; and n is 1 or 2; with theproviso that when A is —CH═C(CH₃)CH₂— or —CH═CHCH₂—, then either: Bcannot be —CH(CH₃)CH═CHCH═CH₂, —CH(CH₃)CH₂Ph, —CH(CH₃)Ph, —CH(CH₃)-n-Bu,

or C cannot be —C(O)N(R₁)R₂ or H; or an acid or base addition saltthereof, where possible.
 2. A compound according to claim 1 of formulaIa

where A′ is —CH═C(R₁′)CH₂—, —CH₂N(R₂′)C(O)—, —C(O)N(R₂′)CH₂—,—CH₂N(CO₂R₃)CH₂— or —CH₂N(COR₂′)CH₂—; B′ is —CH(R₁′)CH═CHCH═CH₂,—CH(R₂′)R₁′, —CH(R₁′)CH═CHR₂′, —CH(R₁′)CH₂OR₂′ or Ar′; C′ is H,—C(O)N(R₁′)R₂′, —C(O)NHCH₂(CH₂)_(n)N(CH₃)₂, or—C(O)NHCH₂(CH₂)_(n)-4-morpholino; R₁′ is H or (C₁)alkyl; R₂′ is H,(C₁)alkyl, (C₂₋₆)alkenyl, (C₂₋₆)alkynyl, (C₁₋₆)alkyl-Ar′ or Ar′; R₃′ is(C₁)alkyl, (C₁₋₆)alkyl-Ar′ or Ar′; Ar′ is an aromatic or heteroaromaticring selected from

R₄₁ and R₁₅ are, independently, H, (C₁)alkyl, OH, O(C₁₋₆)alkyl,OCH₂(CH₂), OH, O(CH₂), CO₂H, OCH₂(CH₂), N(CH₃)₂,OCH₂(CH₂)_(n)-4-morpholino, F, Cl, Br or CF₃; and n is 1 or 2; with theproviso that when A′ is —CH═C(CH₃)CH₂— or —CH═CHCH₂—, then either: B′cannot be —CH(CH₃)CH═CHCH═CH₂, —CH(CH₃)CH₂Ph, —CH(CH₃)Ph, —CH(CH₃)-n-Bu,

or C′ cannot be —C(O)N(R₁′)R₂′ or H; or an acid or base addition saltthereof, where possible.
 3. A compound according to claim 2 of formulaIb

where A″ is —CH═C(R₁″)CH₂—, —CH₂N(R₂″)C(O)— or —C(O)N(R₂″)CH₂—; B″ is—CH(R₁″)CH═CHCH═CH₂, —CH(R₂″)R₁″, —CH(R₁″)CH═CHR₂″, —CH(R₁″)CH₂OR₂″ orAr″; C″ is H, —C(O)N(R₁″)R₂″, —C(O)NHCH₂(CH₂)_(n)N(CH₃)₂ or—C(O)NHCH₂(CH₂)_(n)-4-morpholino; R₁″ is H or —CH₃; R₂″ is H, (C₁)alkyl,(C₂₋₆)alkenyl, (C₂₋₆)alkynyl, (C₁₋₆)alkyl-Ar″ or Ar″; Ar″ is an aromaticor heteroaromatic ring selected from

R₄″ and R₅″ are, independently, H, (C₁₋₆)alkyl, OH, O(C₁₋₆)alkyl,OCH₂(CH₂), OH, O(CH₂)_(r)CO₂H, OCH₂(CH₂)_(n)N(CH₃)₂,OCH₂(CH₂)_(n)-4-morpholino, F, Cl, Br or CF₃; and n is 1 or 2; with theproviso that when A″ is —CH═C(CH₃)CH₂— or —CH═CHCH₂—, then either: B″cannot be —CH(CH₃)CH═CHCH═CH₂, —CH(CH₃)CH₂Ph, —CH(CH₃)Ph, —CH(CH₃)-n-Bu,

or C″ cannot be —C(O)N(R₁″)R₂″ or H; or an acid or base addition saltthereof, where possible.
 4. A compound according to claim 3 of formulaIc

where A′″ is —CH═C(R₁′″)CH₂—, —CH₂N(R₂′″)C(O)— or —C(O)N(R₂′″)CH₂—; B′″is —CH(R₁′″)CH═CHCH═CH₂, —CH(R₂′″)R₁′″, —CH(R₁′″)CH═CHR₂′″,—CH(R₁′″)CH₂OR₂′″ or Ar′″; C′″ is H or —C(O)N(R₁′″)R₂′″; R₁′″ is H orCH₃; R₂′″ is H, (C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₂₋₆)alkynyl,(C₁)alkyl-Ar′″ or Ar′″; Ar′″ is an aromatic ring selected having theformula

R₄′″ and R₅′″ are, independently, H, (C,)alkyl, OH, O(C,;)alkyl, F, Cl,Br or CF₃; with the proviso that when A′″ is —CH═C(CH₃)CH₂— or—CH═CHCH₂—, then either: B′″ cannot be —CH(CH₃)CH═CHCH═CH₂,—CH(CH₃)CH₂Ph, —CH(CH₃)Ph, —CH(CH₃)-n-Bu,

or C′″ cannot be —C(O)N(R₁′″)R₂′″ or H; or an acid or base addition saltthereof, where possible.
 5. A compound according to claim 1 of formula1, or a pharmaceutically acceptable acid or base addition salt thereof,where possible.
 6. A compound according to claim 2 of formula Ia, or apharmaceutically acceptable acid or base addition salt thereof, wherepossible.
 7. A compound according to claim 3 of formula Ib, or apharmaceutically acceptable acid or base addition salt thereof, wherepossible.
 8. A compound according to claim 4 of formula Ic, or apharmaceutically acceptable acid or base addition salt thereof, wherepossible.
 9. A compound selected from19-[(aminocarbonyl)oxy]-3,5,7,11,17-pentahydroxy-2,3,4,10,12,14,16,18,20-nonamethyl-21-(phenylmethoxy)-8,13-heneicosadienoicacid 5-lactone and13-[[5-[(aminocarbonyl)oxy]-3-hydroxy-2,4,6-trimethyl-1-oxo-7,9-decadienyl]methylamino]-3,5,7,11-tetrahydroxy-2,4,10,12-tetramethyl-8-tridecenoicacid 8-lactone, or a pharmaceutically acceptable acid or base additionsalt thereof.
 10. A compound selected from(2R,3S,4S,5S,7S,8Z,10S,11S,12S,13Z,16S,17R,18S,19S,20S)-19-[(aminocarbonyl)oxy]-3,5,7,11,17-pentahydroxy-2,3,4,10,12,14,16,18,20-nonamethyl-21-(phenylmethoxy)-8,13-heneicosadienoicacid 6-lactone and(2R,3S,4R,5S,7S,8Z)-13-[[(2R,3S,4S,5S,6S,7Z)-5-[(aminocarbonyl)oxy]-3-hydroxy-2,4,6-trimethyl-1-oxo-7,9-decadienyl]methylamino]-3,5,7,11-tetrahydroxy-2,4,10,12-tetramethyl-8-tridecenoicacid δ-lactone, or a pharmaceutically acceptable acid or base additionsalt thereof.
 11. A pharmaceutical composition comprising apharmaceutically acceptable carrier or diluent and a therapeuticallyeffective amount of a compound according to claim 5, or apharmaceutically acceptable acid or base addition salt thereof, wherepossible.
 12. A pharmaceutical composition comprising a pharmaceuticallyacceptable carrier or diluent and a therapeutically effective amount ofa compound according to claim 6, or a pharmaceutically acceptable acidor base addition salt thereof, where possible.
 13. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier or diluentand a therapeutically effective amount of a compound according to claim7, or a pharmaceutically acceptable acid or base addition salt thereof,where possible.
 14. A pharmaceutical composition comprising apharmaceutically acceptable carrier or diluent and a therapeuticallyeffective amount of a compound according to claim 8, or apharmaceutically acceptable acid or base addition salt thereof, wherepossible.
 15. A pharmaceutical composition comprising a pharmaceuticallyacceptable carrier or diluent and a therapeutically effective amount ofa compound according to claim 9, or a pharmaceutically acceptable acidor base addition salt thereof, where possible.
 16. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier or diluentand a therapeutically effective amount of a compound according to claim10, or a pharmaceutically acceptable acid or base addition salt thereof,where possible.
 17. A method of treating tumors comprising administeringto a mammal in need of such treatment a therapeutically effective amountof a compound according to claim 5, or a pharmaceutically acceptableacid or base addition salt thereof, where possible.
 18. A method oftreating tumors comprising administering to a mammal in need of suchtreatment a therapeutically effective amount of a compound according toclaim 6, or a pharmaceutically acceptable acid or base addition saltthereof, where possible.
 19. A method of treating tumors comprisingadministering to a mammal in need of such treatment a therapeuticallyeffective amount of a compound according to claim 7, or apharmaceutically acceptable acid or base addition salt thereof, wherepossible.
 20. A method of treating tumors comprising administering to amammal in need of such treatment a therapeutically effective amount of acompound according to claim 8, or a pharmaceutically acceptable acid orbase addition salt thereof, where possible.
 21. A method of treatingtumors comprising administering to a mammal in need of such treatment atherapeutically effective amount of a compound according to claim 9, ora pharmaceutically acceptable acid or base addition salt thereof, wherepossible.
 22. A method of treating tumors comprising administering to amammal in need of such treatment a therapeutically effective amount of acompound according to claim 10, or a pharmaceutically acceptable acid orbase addition salt thereof, where possible.